VCV000012602.63 - ClinVar

NM_005343.4(HRAS):c.34G>A (p.Gly12Ser)

Germline

Top reviewed classifications are shown here.

Submission summary:

69 submissions

41 submitters

39 conditions

Reviewed by expert panel

Pathogenic

Apr 2017 by ClinGen RASopa… FDA Recognized Database

for Costello syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005343.4(HRAS):c.34G>A (p.Gly12Ser)

Variation ID: 12602 Accession: VCV000012602.63

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.5 11: 534289 (GRCh38) [ NCBI UCSC ] 11: 534289 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 16, 2015	Oct 8, 2024	Apr 3, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_005343.4:c.34G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005334.1:p.Gly12Ser	missense
NM_176795.5:c.34G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_789765.1:p.Gly12Ser	missense
NM_001130442.3:c.34G>A	NP_001123914.1:p.Gly12Ser	missense
NM_001318054.2:c.-286G>A		5 prime UTR
NC_000011.10:g.534289C>T
NC_000011.9:g.534289C>T
NG_007666.1:g.6262G>A
LRG_506:g.6262G>A
LRG_506t1:c.34G>A	LRG_506p1:p.Gly12Ser
	P01112:p.Gly12Ser

... more HGVS ... less HGVS

Protein change

G12S

Other names

p.G12S:GGC>AGC
NM_005343.3(HRAS):c.34G>A

Canonical SPDI

NC_000011.10:534288:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA122549 UniProtKB: P01112#VAR_006837 OMIM: 190020.0003 dbSNP: rs104894229 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HRAS		No evidence available	No evidence available	GRCh38 GRCh38 GRCh37	12	725
LRRC56		-	-	GRCh38 GRCh38 GRCh37	346	1059

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Myopathy, congenital, with excess of muscle spindles	Pathogenic (1)	no assertion criteria provided	Apr 1, 2014	RCV000013436.34
Costello syndrome	Pathogenic (24)	reviewed by expert panel	Apr 3, 2017	RCV000013435.78
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Mar 10, 2021	RCV000081295.29
RASopathy	Pathogenic (1)	no assertion criteria provided	-	RCV000149828.10
Breast neoplasm	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000430608.9
Transitional cell carcinoma of the bladder	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000435163.9
Myelodysplastic syndrome	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000440863.9
Adenoid cystic carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000440993.9
Carcinoma of esophagus	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000445039.9
Epidermal nevus with urothelial cancer, somatic	Pathogenic (1)	no assertion criteria provided	Apr 1, 2014	RCV000022796.15
Nevus sebaceous	Pathogenic (1)	no assertion criteria provided	Apr 1, 2014	RCV000029209.16
Uterine carcinosarcoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000417494.9
Thyroid tumor	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000425542.9
Papillary renal cell carcinoma, sporadic	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000432342.9
Squamous cell carcinoma of the skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000432945.9
Nasopharyngeal neoplasm	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000422253.9
Multiple myeloma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000440297.9
Malignant neoplasm of body of uterus	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000430725.9
Neoplasm of the large intestine	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000443940.9
Pancreatic adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000433576.9
Neoplasm of uterine cervix	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000438022.9
Malignant melanoma of skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000419709.9
Lung adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000420366.9
Acute myeloid leukemia	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000422656.9
Gastric adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000423310.9
Squamous cell carcinoma of the head and neck	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000424896.9
Prostate adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000427772.9
Ovarian serous cystadenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000430011.9
Glioblastoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000432984.9
Hepatocellular carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000440237.9
Wooly hair nevus	Pathogenic (1)	no assertion criteria provided	Apr 1, 2014	RCV000487471.10
Rhabdomyosarcoma	Pathogenic (1)	no assertion criteria provided	Sep 1, 2020	RCV001257537.9
Noonan syndrome and Noonan-related syndrome	Pathogenic (1)	criteria provided, single submitter	Dec 19, 2016	RCV001813185.11
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Aug 8, 2023	RCV002453256.10
Lip and oral cavity carcinoma	Pathogenic (1)	no assertion criteria provided	Apr 30, 2019	RCV001255689.9
See cases	Pathogenic (1)	criteria provided, single submitter	Dec 21, 2022	RCV003156059.8
HRAS-related disorder	Pathogenic (1)	no assertion criteria provided	Jan 29, 2024	RCV003398496.6
Noonan syndrome 1	Pathogenic (2)	criteria provided, single submitter	-	RCV003450635.2
Epidermal nevus	Pathogenic (1)	criteria provided, single submitter	Sep 7, 2023	RCV003450636.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 03, 2017)	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1) Method: curation	Costello syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen RASopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV000616364.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022	Publications: PubMed (15) PubMed: 16329078‚ 16969868‚ 19206176‚ 16835863‚ 16170316‚ 18039947‚ 19669404‚ 29493581‚ 20660566‚ 19371735‚ 16443854‚ 17054105‚ 16372351‚ 16881968‚ 17412879 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/51947641-2e77-498f-93d6-ca73b8e343de Comment: The c.34G>A (p.Gly12Ser) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a … (more) The c.34G>A (p.Gly12Ser) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 16170316, 16835863, 16443854, 16835863, 16881968, 17054105, 19669404). The p.Gly12Ser variant has been identified in >5 independent occurrences in patients with clinical features of a RASopathy (PS4; PMID: 20660566, 16372351, 16329078, 16969868, 18039947, 19371735, 19206176, 16835863). In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact protein function (PS3; PMID: 17412879). Computational prediction tools and conservation analysis suggest that the p.Gly12Ser variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PS3, PM1, PM2, PP2, PP3. (less)
Pathogenic (Apr 01, 2015)	criteria provided, single submitter (Variant Classification) Method: clinical testing	Costello syndrome Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000263952.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 26, 2017	Publications: PubMed (14) PubMed: 16170316‚ 16329078‚ 16372351‚ 16443854‚ 16835863‚ 16881968‚ 17054105‚ 17412879‚ 18039947‚ 19206176‚ 19371735‚ 19669404‚ 20660566‚ 21850009 Number of individuals with the variant: 1
Pathogenic (Jul 30, 2012)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Costello syndrome Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000062131.5 First in ClinVar: May 03, 2013 Last updated: Dec 26, 2017	Publications: PubMed (15) PubMed: 16372351‚ 16170316‚ 16329078‚ 16443854‚ 17054105‚ 19371735‚ 20660566‚ 16969868‚ 18039947‚ 18978862‚ 16835863‚ 19206176‚ 17412879‚ 16881968‚ 19669404 Comment: The Gly12Ser variant in HRAS is the most common variant associated with Costello syndrome (Aoki 2005, Kerr 2006, Gripp 2006, Gori 2008, Dileone 2010, Estep … (more) The Gly12Ser variant in HRAS is the most common variant associated with Costello syndrome (Aoki 2005, Kerr 2006, Gripp 2006, Gori 2008, Dileone 2010, Estep 2006 , Gripp 2006, Lo 2008, Paquin 2009, Sol-Church 2009, Sol-Church 2006, van der Bu rgt 2007, van Steensel 2006, Zampino 2007, Zhang 2009). This variant has been re ported to have occurred de novo in many individuals. In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). (less) Number of individuals with the variant: 13
Pathogenic (Jul 03, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	COSTELLO SYNDROME Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV000996166.1 First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019	Comment: This established pathogenic variant is found in approximately 80% of individuals with Costello syndrome (PMID: 16170316, 22261753, 20301680). This variant has been classified in ClinVar … (more) This established pathogenic variant is found in approximately 80% of individuals with Costello syndrome (PMID: 16170316, 22261753, 20301680). This variant has been classified in ClinVar as pathogenic by the ClinGen Rasopathy Expert Panel and by several clinical diagnostic laboratories (variant ID: 12602). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.34G>A (p.Gly12Ser) variant is classified as pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (Jan 11, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Genomic Medicine Lab, University of California San Francisco Study: CSER Accession: SCV001167662.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Secondary finding: no
Pathogenic (Apr 06, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Costello syndrome Affected status: yes Allele origin: germline	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV001423659.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020	Comment: [ACMG/AMP: PS2, PM1, PM2, PM5, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) … (more) [ACMG/AMP: PS2, PM1, PM2, PM5, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. (less)
Pathogenic (Feb 16, 2020)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000603969.3 First in ClinVar: Sep 30, 2017 Last updated: Jan 26, 2021	Comment: The HRAS c.34G>A; p.Gly12Ser variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr … (more) The HRAS c.34G>A; p.Gly12Ser variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011, Zampino 2007). The glycine residues at codons 12 and 13 are frequently altered in both Costello syndrome patients (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011) and tumor samples (Aoki 2005, Estep 2006). Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011), consistent with the established disease mechanism of Costello syndrome, which has phenotypic overlap with Noonan syndrome. Based on available information, this variant is considered to be pathogenic. References: Aoki Y et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005; 37(10):1038-40. Estep A et al. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A. 2006; 140(1):8-16. Gripp K et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006; 140(1):1-7. Kerr B et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006; 43(5):401-5. Niihori T et al. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. J Hum Genet. 2011; 56(10):707-15. Zampino G et al. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat. 2007; 28(3):265-72. (less)
Pathogenic (Oct 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV001520829.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Nov 29, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000207842.11 First in ClinVar: Mar 24, 2015 Last updated: Feb 17, 2019	Comment: Functional studies indicate that the G12S variant alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which up-regulates the Ras/MAPK pathway (Wey … (more) Functional studies indicate that the G12S variant alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which up-regulates the Ras/MAPK pathway (Wey et al. 2013); Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Classified as pathogenic by the ClinGen RASopathy Expert Panel (SCV000616364.3; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 22317973, 27195699, 21850009, 24224811, 23093928, 16329078, 16170316, 19371735, 23751039, 21834037, 20979192, 27705751, 26350204, 24803665, 27589201, 25722179, 24169525, 28141901, 28027064, 16835863, 17412879, 16881968, 19669404, 30138938, 30055033, 30792901, 30050098, 25815234, 31394527, 29907801, 31560489, 31564432, 31712860, 31965297, 31795565, 32369273, 32371413, 33482860, 32681669) (less)
Pathogenic (Oct 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: yes Allele origin: unknown	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV001976682.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021	Publications: PubMed (1) PubMed: 34008892 Comment: PS1, PM1, PM2, PM5, PP2, PP3, PP5
Pathogenic (Mar 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059320.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Pathogenic (Sep 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580200.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS2, PS4, PM5, PM2_SUP	Number of individuals with the variant: 1 Sex: female
Pathogenic (Mar 10, 2021)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV002817295.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Comment: Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID 28139825). This variant has not been reported in large, multi-ethnic general populations … (more) Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID 28139825). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in approximately 80% of individuals with Costello syndrome and is reported to be the most frequent pathogenic variant in the HRAS gene (PMID: 21834037, 20979192, 17054105, 16881968, 16372351, 16170316, 16329078, 16443854). This variant occurs de novo in an individual tested at Athena Diagnostics and in previously reported individuals with clinical features of Costello syndrome (PMID: 16170316, 16372351, 16881968, 17054105, 21834037, 28027064). Germline mosaicism has been reported as an inheritance mechanism for multiple cases, with the majority arising in the paternal germline (PMID: 24259709, 16835863, 21834037).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. (less)
Pathogenic (Dec 18, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center Accession: SCV004037370.1 First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023	Publications: PubMed (5) PubMed: 16170316‚ 16835863‚ 16443854‚ 16881968‚ 17054105 Comment: The missense variant c.34G>A results in a single base pair substitution at nucleotide position 34 in exon 2 (6 in total) of_x000D_the HRAS gene. The … (more) The missense variant c.34G>A results in a single base pair substitution at nucleotide position 34 in exon 2 (6 in total) of_x000D_the HRAS gene. The c.34G>A variant is not observed in the Genome Aggregation Database (gnomAD), indicating it is_x000D_not a common benign variant in the populations represented in this database._x000D_The variant is a well-defined pathogenic variant associated with Costello syndrome (PMID:NBK1507), and has been_x000D_described as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (VarID: 12602). It has been reported_x000D_previously in multiple patients with features of RASopathy (PMID: 16170316, 16835863, 16443854, 16881968,_x000D_17054105). The variant is located in a mutational hotspot region, which harbors very low rate of benign missense_x000D_mutations. This variant is predicted to be deleterious by multiple computational tools. Additionally, in vitro functional_x000D_studies have demonstrated that this variant may affect protein function (PMID: 17412879) (less) Clinical Features: Abnormal heart morphology (present) , Multifocal atrial tachycardia (present) , Pleural effusion (present) , Respiratory insufficiency (present) , Respiratory insufficiency (present) , Immunodeficiency (present) , … (more) Abnormal heart morphology (present) , Multifocal atrial tachycardia (present) , Pleural effusion (present) , Respiratory insufficiency (present) , Respiratory insufficiency (present) , Immunodeficiency (present) , Hypotonia (present) , Global developmental delay (present) , Failure to thrive (present) (less) Age: 0-9 years Sex: female Tissue: DNA
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004171305.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023	Comment: The missense c.34G>A(p.Gly12Ser) variant in HRAS gene has been reported previously in individual(s) affected with Costello syndrome (Niihori T, et. al., 2011; Aoki Y, et. … (more) The missense c.34G>A(p.Gly12Ser) variant in HRAS gene has been reported previously in individual(s) affected with Costello syndrome (Niihori T, et. al., 2011; Aoki Y, et. al., 2005). Functional studies indicate this variant has a damaging effect on the gene or the gene product (van der Burgt I, et. al., 2007). The p.Gly12Ser variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid Gly at position 12 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Epidermal nevus Affected status: yes Allele origin: somatic	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV004176909.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: An HRAS c.34G>A (p.Gly12Ser) variant was identified. This variant has been reported in numerous individuals with epidermal nevus (Hafner C et al., PMID: 22087699; Farschtschi … (more) An HRAS c.34G>A (p.Gly12Ser) variant was identified. This variant has been reported in numerous individuals with epidermal nevus (Hafner C et al., PMID: 22087699; Farschtschi S et al., PMID: 25928347; Nishihara K et al., PMID: 30864170; Levinsohn JL et al., PMID: 24129065; Honda A et al., PMID: 28295558; Bender RP et al., PMID: 23599145). This variant has been reported in the ClinVar database as a germline pathogenic variant by numerous submitters, including an expert panel (ClinVar ID: 12602) and has been reported as a somatic variant in multiple cases in the cancer database cBioPortal. This variant is absent from the general population (gnomAD v.3.1.2), indicating that it is not a common variant. Other variants in the same codon, (p.Gly12Arg, p.Gly12Cys, p.Gly12Val, p.Gly12Ala, p.Gly12Asp), have been reported as pathogenic/likely pathogenic [ClinVar ID: 375961, 12613, 12600, 1209208, 12603, 40430, 12612]. The HRAS c.34G>A (p.Gly12Ser) variant resides within an H_N_K_Ras_like domain, amino acids 3-164, of HRAS that is defined as a critical functional domain (Wey M et al., PMID: 24224811). Functional studies show that this variant promotes enhanced MEK, ERK, and AKT phosphorylation and growth-factor independent proliferation, indicating that this variant impacts protein function (Gremer L et al., PMID: 19995790; Denayer E et al., PMID: 17979197). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to HRAS function. The HRAS gene is defined by ClinGen's RASopathy expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Gelb BD et al., PMID: 29493581). Based on the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the HRAS c.34G>A (p.Gly12Ser) variant is classified as pathogenic. (less)
Pathogenic (Oct 29, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002025029.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Oct 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Costello syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000288856.9 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 16170316‚ 20979192‚ 21834037‚ 21850009‚ 22317973‚ 23751039 Comment: This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the HRAS protein (p.Gly12Ser). … (more) This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the HRAS protein (p.Gly12Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12602). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt HRAS function. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 24, 2018)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Costello syndrome Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV004801624.1 First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024	Comment: The HRAS c.34G>A p.(Gly12Ser) missense variant has been identified in individuals with a phenotype consistent with Costello syndrome, and in a de novo state in … (more) The HRAS c.34G>A p.(Gly12Ser) missense variant has been identified in individuals with a phenotype consistent with Costello syndrome, and in a de novo state in the majority (Gripp et al. 2006; Hague et al. 2017; Chiu et al. 2016; Niihori et al. 2011; van Steensel et al. 2006). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The Gly12 residue is highly conserved through evolution. Functional studies found that when the p.Gly12Ser variant HRAS protein was over-expressed in human diploid fibroblasts, cells exhibited a senescence phenotype including a flat, enlarged and multivacuolated morphology with prominent nucleoli, in contrast to cells produced by wild type HRAS protein (Niihori et al. 2011). In addition, cells expressing the p.Gly12Ser variant HRAS protein exhibited increased cell proliferation and astrogenesis, but decreased neurogenesis (Paquin et al. 2009). The variant was identified in a de novo state in the proband. Based on the available evidence, the p.Gly12Ser variant is classified as pathogenic for Costello syndrome. (less)
Pathogenic (Jul 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV000680007.2 First in ClinVar: Dec 26, 2017 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 20301680‚ 31222966 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Costello syndrome and congenital myopathy with excess of muscle spindles (MIM#218040) (PMID: 31222966). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301680). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple alternative changes at this residue have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel and multiple clinical laboratories in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Centre for Human Genetics Accession: SCV005199936.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024	Comment: The HRAS c.34G>A(p.Gly12Ser) variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, … (more) The HRAS c.34G>A(p.Gly12Ser) variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011, Zampino 2007). Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011), consistent with the established disease mechanism of Costello syndrome, which has phenotypic overlap with Noonan syndrome. Based on available information, this variant is considered to be pathogenic. (less) Number of individuals with the variant: 2 Secondary finding: no
Pathogenic (Jun 04, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: yes Allele origin: unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV000263052.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (9) PubMed: 18039947‚ 16170316‚ 16443854‚ 17054105‚ 16372351‚ 16329078‚ 16969868‚ 19206176‚ 16881968 Observation 1: Number of individuals with the variant: 1 Clinical Features: none provided (present) Age: 0-9 years Sex: male Observation 2: Number of individuals with the variant: 1 Clinical Features: failure to thrive, feeding issues, multiple papillomata, skeletal anomalies, foot deformities, developmental delay (present) Age: 0-9 years Sex: male Observation 3: Number of individuals with the variant: 1 Clinical Features: clinical features of Costello Syndrome (present) , subglottic stenosis (present) Age: 0-9 years Sex: female Observation 4: Number of individuals with the variant: 1 Clinical Features: none provided (present) Age: 10-19 years Sex: male Observation 5: Number of individuals with the variant: 1 Clinical Features: dysmorphic at birth, developed seizures, atrial septal defect, coarctation of the aorta, hypotonia, gastroesophageal refulx disease, developmental delay (present) Age: 0-9 years Sex: male Observation 6: Number of individuals with the variant: 1 Clinical Features: coarse facial features, macroglossia, failure to thrive, redundant skin on plams, atrial tachycardia (present) Age: 0-9 years Sex: female Observation 7: Number of individuals with the variant: 1 Age: 0-9 years Sex: female Observation 8: Number of individuals with the variant: 1 Clinical Features: Coarse facial features (present) , Congestive heart failure (present) , Feeding tube (present) , Moderate to profound mental retardation (present) , Polyhydramnios in utero (present) Age: 10-19 years Sex: male Observation 9: Number of individuals with the variant: 1 Age: 0-9 years Sex: female Observation 10: Number of individuals with the variant: 1 Clinical Features: Coarse facial features (present) , Deep palmar creases (present) , Redundant skin on scalp (present) , Pulmonic stenosis (present) Age: 0-9 years Sex: male Observation 11: Number of individuals with the variant: 1 Clinical Features: Coarse facies (present) , Hydrocephalus (present) , Hypertrophic cardiomyopathy (present) , Growth hormone deficiency (present) , Scoliosis (present) , Papilloma (present) Age: 0-9 years Sex: male
Pathogenic (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000781527.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017
Pathogenic (Aug 27, 2015)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227361.5 First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HRAS Number of individuals with the variant: 3 Sex: mixed
Pathogenic (May 13, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Costello syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001362310.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (6) PubMed: 16170316‚ 18247425‚ 16443854‚ 19371735‚ 21850009‚ 28139825 Comment: Variant summary: HRAS c.34G>A (p.Gly12Ser) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three … (more) Variant summary: HRAS c.34G>A (p.Gly12Ser) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250394 control chromosomes (gnomAD). The variant, c.34G>A, has been reported in the literature in multiple individuals affected with Costello Syndrome (Aoki_2005, Kerr_2006, Gripp_2006, Niihori_2011). These data indicate that the variant is very likely to be associated with disease. At least two publication report experimental evidence evaluating an impact on protein function (Gain of function) and the effect of this variant is similar to other HRAS pathogenic variants (Paquin_2009, Niihori_2011). Eight ClinVar submissions from clinical diagnostic laboratories and one expert panel (ClinGen RASopathy) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002058657.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 16835863, 20660566, 19206176, 16329078, 16969868, 19371735, 18039947, 16372351, PS4_S). Functional studies provide strong … (more) The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 16835863, 20660566, 19206176, 16329078, 16969868, 19371735, 18039947, 16372351, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17412879, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.695, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Costello syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012600, VCV000012603, VCV000012612, VCV000012613, VCV000040430, VCV000163690, VCV000180854, VCV000279921, VCV001209208, PM5_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012602, PS1_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Delayed myelination (present) , Downslanted palpebral fissures (present) , Abnormal facial shape (present) , Failure to thrive (present) , Feeding difficulties (present) , Depressed nasal … (more) Delayed myelination (present) , Downslanted palpebral fissures (present) , Abnormal facial shape (present) , Failure to thrive (present) , Feeding difficulties (present) , Depressed nasal bridge (present) , Frontal bossing (present) , Full cheeks (present) , High, narrow palate (present) , Hypertelorism (present) , Generalized hypotonia (present) , Abnormality of limbs (present) , Low-set ears (present) , Relative macrocephaly (present) , Mild short stature (present) , Short chin (present) , Myopathy (present) , Short stature (present) (less)
Pathogenic (Dec 19, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome and Noonan-related syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002060955.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (Jun 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002568185.1 First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022	Comment: PS2 PS3 PS4 PM2 PM5
Pathogenic (Dec 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: unknown	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV003845220.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023	Clinical Features: Abnormal pinna morphology (present) , Abnormal thorax morphology (present) , Arthrogryposis-like hand anomaly (present) , Camptodactyly (present) , Hepatoblastoma (present) , Narrow chest (present) , … (more) Abnormal pinna morphology (present) , Abnormal thorax morphology (present) , Arthrogryposis-like hand anomaly (present) , Camptodactyly (present) , Hepatoblastoma (present) , Narrow chest (present) , Paroxysmal atrial tachycardia (present) , Pectus excavatum (present) (less)
Pathogenic (Aug 08, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002615093.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (10) PubMed: 16155195‚ 16170316‚ 16329078‚ 18039947‚ 19371735‚ 21850009‚ 22317973‚ 22495892‚ 24224811‚ 25914166 Comment: The c.34G>A (p.G12S) alteration is located in exon 2 (coding exon 1) of the HRAS gene. This alteration results from a G to A substitution … (more) The c.34G>A (p.G12S) alteration is located in exon 2 (coding exon 1) of the HRAS gene. This alteration results from a G to A substitution at nucleotide position 34, causing the glycine (G) at amino acid position 12 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration and several other alterations at the same codon (p.G12A, p.G12C, p.G12D, p.G12E, and p.G12V) have been reported in individuals with HRAS-related RASopathy including many de novo occurrences (Aoki, 2005; Hoornaert, 2006; Gripp, 2006; Lo, 2008; Burkitt-Wright, 2012). The p.G12S alteration is the most prevalent alteration reported in patients with HRAS-related RASopathy (reviewed in Wey, 2013). This amino acid position is highly conserved in available vertebrate species. The p.G12 amino acid is located within the phosphate-binding loop of the GTP-binding site (Gripp, 2006). Functional analysis demonstrated that protein products containing the p.G12S alteration have increased binding of GTP, resulting in increased amounts of the active form the HRAS protein (Wey, 2013). Additionally, patient cell lines with the p.G12S alteration were found to have reduced expression of C4ST-1 mRNA compared to wild type (Kluppel 2012), and in vivo studies showed abnormal neuronal cell proliferation and astrogenesis (Paquin, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Rasopathy Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV000196672.1 First in ClinVar: Jan 16, 2015 Last updated: Jan 16, 2015	Publications: PubMed (1) PubMed: 16170316 Comment: Variant classified using ACMG guidelines
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Pancreatic adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506475.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Gastric adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506474.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Malignant neoplasm of body of uterus (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506472.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Adenoid cystic carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506473.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Glioblastoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506478.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Multiple myeloma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506476.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Carcinoma of esophagus (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506479.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506483.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Acute myeloid leukemia (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506477.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Papillary renal cell carcinoma, sporadic (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506481.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of the large intestine (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506482.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of uterine cervix (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506487.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Thyroid tumor (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506480.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Prostate adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506486.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506488.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Malignant melanoma of skin (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506491.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Transitional cell carcinoma of the bladder (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506484.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Hepatocellular carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506493.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Uterine carcinosarcoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506485.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Squamous cell carcinoma of the skin (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506495.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Breast neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506489.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Myelodysplastic syndrome (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506490.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Ovarian serous cystadenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506492.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Nasopharyngeal neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506494.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A
Pathogenic (Apr 01, 2014)	no assertion criteria provided Method: literature only	MYOPATHY, CONGENITAL, WITH EXCESS OF MUSCLE SPINDLES Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000033683.5 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (9) PubMed: 16170316‚ 16443854‚ 17054105‚ 18039947‚ 17412879‚ 11150980‚ 22087699‚ 22683711‚ 24129065 Comment on evidence: Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the … (more) Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)
Pathogenic (Apr 01, 2014)	no assertion criteria provided Method: literature only	EPIDERMAL NEVUS WITH UROTHELIAL CANCER, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000044085.5 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (9) PubMed: 16170316‚ 16443854‚ 17054105‚ 18039947‚ 17412879‚ 11150980‚ 22087699‚ 22683711‚ 24129065 Comment on evidence: Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the … (more) Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)
Pathogenic (Apr 01, 2014)	no assertion criteria provided Method: literature only	NEVUS SEBACEOUS, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000051855.5 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (9) PubMed: 16170316‚ 16443854‚ 17054105‚ 18039947‚ 17412879‚ 11150980‚ 22087699‚ 22683711‚ 24129065 Comment on evidence: Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the … (more) Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)
Pathogenic (Apr 01, 2014)	no assertion criteria provided Method: literature only	NEVUS, WOOLLY HAIR, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000574678.2 First in ClinVar: May 01, 2017 Last updated: Dec 15, 2018	Publications: PubMed (9) PubMed: 16170316‚ 16443854‚ 17054105‚ 18039947‚ 17412879‚ 11150980‚ 22087699‚ 22683711‚ 24129065 Comment on evidence: Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the … (more) Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)
Pathogenic (Apr 01, 2014)	no assertion criteria provided Method: literature only	COSTELLO SYNDROME Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000033682.5 First in ClinVar: Apr 04, 2013 Last updated: Dec 26, 2017	Publications: PubMed (9) PubMed: 16170316‚ 16443854‚ 17054105‚ 18039947‚ 17412879‚ 11150980‚ 22087699‚ 22683711‚ 24129065 Comment on evidence: Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the … (more) Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)
Pathogenic (Sep 01, 2020)	no assertion criteria provided Method: provider interpretation	Rhabdomyosarcoma Affected status: yes Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV001434363.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (1) PubMed: 33372952
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001809092.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955792.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001967870.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Oct 14, 2021)	no assertion criteria provided Method: research	Costello syndrome Affected status: yes Allele origin: germline	Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University Accession: SCV003844076.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Clinical Features: Increased nuchal translucency (present) , Cystic hygroma (present)
Pathogenic (Jan 29, 2024)	no assertion criteria provided Method: clinical testing	HRAS-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004104104.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The HRAS c.34G>A variant is predicted to result in the amino acid substitution p.Gly12Ser. This variant is one of the most frequent pathogenic variants in … (more) The HRAS c.34G>A variant is predicted to result in the amino acid substitution p.Gly12Ser. This variant is one of the most frequent pathogenic variants in HRAS and has been documented as a de novo event in multiple unrelated individuals with Costello Syndrome (for examples see - Aoki et. al. 2005. PubMed ID: 17177115; Gripp et al. 2011. PubMed ID: 21834037). Additionally, different amino acid substitutions (p.Gly12Arg, p.Gly12Cys, p.Gly12Asp, p.Gly12Ala, p.Gly12Val) affecting the same amino acid have been reported as pathogenic (Human Gene Mutation Database). Functional studies demonstrate increased GTP-bound HRAS (active state) in cells transfected with the p.Gly12Ser variant, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Niihori et al. 2011. PubMed ID: 21850009). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted by multiple labs and the ClinGen RASopathy Variant Curation Expert Panel as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12602/). This variant is interpreted as pathogenic. (less)
Pathogenic (Dec 18, 2017)	no assertion criteria provided Method: clinical testing	Costello syndrome Affected status: yes Allele origin: germline	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital Accession: SCV000805105.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017
Pathogenic (Apr 30, 2019)	no assertion criteria provided Method: research	Lip and oral cavity carcinoma Affected status: yes Allele origin: somatic	Institute of Medical Sciences, Banaras Hindu University Accession: SCV001432254.1 First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020	Publications: PubMed (1) PubMed: 31775759 Number of individuals with the variant: 3
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Noonan syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Molecular Genetics, Centre for Human Genetics Accession: SCV004190105.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Number of individuals with the variant: 6 Secondary finding: no
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Comment:

The c.34G>A (p.Gly12Ser) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 16170316, 16835863, 16443854, 16835863, 16881968, 17054105, 19669404). The p.Gly12Ser variant has been identified in >5 independent occurrences in patients with clinical features of a RASopathy (PS4; PMID: 20660566, 16372351, 16329078, 16969868, 18039947, 19371735, 19206176, 16835863). In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact protein function (PS3; PMID: 17412879). Computational prediction tools and conservation analysis suggest that the p.Gly12Ser variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PS3, PM1, PM2, PP2, PP3.

Comment:

The Gly12Ser variant in HRAS is the most common variant associated with Costello syndrome (Aoki 2005, Kerr 2006, Gripp 2006, Gori 2008, Dileone 2010, Estep 2006 , Gripp 2006, Lo 2008, Paquin 2009, Sol-Church 2009, Sol-Church 2006, van der Bu rgt 2007, van Steensel 2006, Zampino 2007, Zhang 2009). This variant has been re ported to have occurred de novo in many individuals. In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).

Comment:

This established pathogenic variant is found in approximately 80% of individuals with Costello syndrome (PMID: 16170316, 22261753, 20301680). This variant has been classified in ClinVar as pathogenic by the ClinGen Rasopathy Expert Panel and by several clinical diagnostic laboratories (variant ID: 12602). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.34G>A (p.Gly12Ser) variant is classified as pathogenic.

Comment:

[ACMG/AMP: PS2, PM1, PM2, PM5, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].

Comment:

The HRAS c.34G>A; p.Gly12Ser variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011, Zampino 2007). The glycine residues at codons 12 and 13 are frequently altered in both Costello syndrome patients (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011) and tumor samples (Aoki 2005, Estep 2006). Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011), consistent with the established disease mechanism of Costello syndrome, which has phenotypic overlap with Noonan syndrome. Based on available information, this variant is considered to be pathogenic. References: Aoki Y et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005; 37(10):1038-40. Estep A et al. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A. 2006; 140(1):8-16. Gripp K et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006; 140(1):1-7. Kerr B et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006; 43(5):401-5. Niihori T et al. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. J Hum Genet. 2011; 56(10):707-15. Zampino G et al. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat. 2007; 28(3):265-72.

Comment:

Functional studies indicate that the G12S variant alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which up-regulates the Ras/MAPK pathway (Wey et al. 2013); Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Classified as pathogenic by the ClinGen RASopathy Expert Panel (SCV000616364.3; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 22317973, 27195699, 21850009, 24224811, 23093928, 16329078, 16170316, 19371735, 23751039, 21834037, 20979192, 27705751, 26350204, 24803665, 27589201, 25722179, 24169525, 28141901, 28027064, 16835863, 17412879, 16881968, 19669404, 30138938, 30055033, 30792901, 30050098, 25815234, 31394527, 29907801, 31560489, 31564432, 31712860, 31965297, 31795565, 32369273, 32371413, 33482860, 32681669)

Comment:

Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID 28139825). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in approximately 80% of individuals with Costello syndrome and is reported to be the most frequent pathogenic variant in the HRAS gene (PMID: 21834037, 20979192, 17054105, 16881968, 16372351, 16170316, 16329078, 16443854). This variant occurs de novo in an individual tested at Athena Diagnostics and in previously reported individuals with clinical features of Costello syndrome (PMID: 16170316, 16372351, 16881968, 17054105, 21834037, 28027064). Germline mosaicism has been reported as an inheritance mechanism for multiple cases, with the majority arising in the paternal germline (PMID: 24259709, 16835863, 21834037).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

Comment:

The missense variant c.34G>A results in a single base pair substitution at nucleotide position 34 in exon 2 (6 in total) of_x000D_the HRAS gene. The c.34G>A variant is not observed in the Genome Aggregation Database (gnomAD), indicating it is_x000D_not a common benign variant in the populations represented in this database._x000D_The variant is a well-defined pathogenic variant associated with Costello syndrome (PMID:NBK1507), and has been_x000D_described as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (VarID: 12602). It has been reported_x000D_previously in multiple patients with features of RASopathy (PMID: 16170316, 16835863, 16443854, 16881968,_x000D_17054105). The variant is located in a mutational hotspot region, which harbors very low rate of benign missense_x000D_mutations. This variant is predicted to be deleterious by multiple computational tools. Additionally, in vitro functional_x000D_studies have demonstrated that this variant may affect protein function (PMID: 17412879)

Comment:

The missense c.34G>A(p.Gly12Ser) variant in HRAS gene has been reported previously in individual(s) affected with Costello syndrome (Niihori T, et. al., 2011; Aoki Y, et. al., 2005). Functional studies indicate this variant has a damaging effect on the gene or the gene product (van der Burgt I, et. al., 2007). The p.Gly12Ser variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid Gly at position 12 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

Comment:

An HRAS c.34G>A (p.Gly12Ser) variant was identified. This variant has been reported in numerous individuals with epidermal nevus (Hafner C et al., PMID: 22087699; Farschtschi S et al., PMID: 25928347; Nishihara K et al., PMID: 30864170; Levinsohn JL et al., PMID: 24129065; Honda A et al., PMID: 28295558; Bender RP et al., PMID: 23599145). This variant has been reported in the ClinVar database as a germline pathogenic variant by numerous submitters, including an expert panel (ClinVar ID: 12602) and has been reported as a somatic variant in multiple cases in the cancer database cBioPortal. This variant is absent from the general population (gnomAD v.3.1.2), indicating that it is not a common variant. Other variants in the same codon, (p.Gly12Arg, p.Gly12Cys, p.Gly12Val, p.Gly12Ala, p.Gly12Asp), have been reported as pathogenic/likely pathogenic [ClinVar ID: 375961, 12613, 12600, 1209208, 12603, 40430, 12612]. The HRAS c.34G>A (p.Gly12Ser) variant resides within an H_N_K_Ras_like domain, amino acids 3-164, of HRAS that is defined as a critical functional domain (Wey M et al., PMID: 24224811). Functional studies show that this variant promotes enhanced MEK, ERK, and AKT phosphorylation and growth-factor independent proliferation, indicating that this variant impacts protein function (Gremer L et al., PMID: 19995790; Denayer E et al., PMID: 17979197). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to HRAS function. The HRAS gene is defined by ClinGen's RASopathy expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Gelb BD et al., PMID: 29493581). Based on the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the HRAS c.34G>A (p.Gly12Ser) variant is classified as pathogenic.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the HRAS protein (p.Gly12Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12602). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt HRAS function. For these reasons, this variant has been classified as Pathogenic.

Comment:

The HRAS c.34G>A p.(Gly12Ser) missense variant has been identified in individuals with a phenotype consistent with Costello syndrome, and in a de novo state in the majority (Gripp et al. 2006; Hague et al. 2017; Chiu et al. 2016; Niihori et al. 2011; van Steensel et al. 2006). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The Gly12 residue is highly conserved through evolution. Functional studies found that when the p.Gly12Ser variant HRAS protein was over-expressed in human diploid fibroblasts, cells exhibited a senescence phenotype including a flat, enlarged and multivacuolated morphology with prominent nucleoli, in contrast to cells produced by wild type HRAS protein (Niihori et al. 2011). In addition, cells expressing the p.Gly12Ser variant HRAS protein exhibited increased cell proliferation and astrogenesis, but decreased neurogenesis (Paquin et al. 2009). The variant was identified in a de novo state in the proband. Based on the available evidence, the p.Gly12Ser variant is classified as pathogenic for Costello syndrome.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Costello syndrome and congenital myopathy with excess of muscle spindles (MIM#218040) (PMID: 31222966). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301680). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple alternative changes at this residue have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel and multiple clinical laboratories in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The HRAS c.34G>A(p.Gly12Ser) variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011, Zampino 2007). Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011), consistent with the established disease mechanism of Costello syndrome, which has phenotypic overlap with Noonan syndrome. Based on available information, this variant is considered to be pathogenic.

Comment:

Variant summary: HRAS c.34G>A (p.Gly12Ser) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250394 control chromosomes (gnomAD). The variant, c.34G>A, has been reported in the literature in multiple individuals affected with Costello Syndrome (Aoki_2005, Kerr_2006, Gripp_2006, Niihori_2011). These data indicate that the variant is very likely to be associated with disease. At least two publication report experimental evidence evaluating an impact on protein function (Gain of function) and the effect of this variant is similar to other HRAS pathogenic variants (Paquin_2009, Niihori_2011). Eight ClinVar submissions from clinical diagnostic laboratories and one expert panel (ClinGen RASopathy) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 16835863, 20660566, 19206176, 16329078, 16969868, 19371735, 18039947, 16372351, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17412879, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.695, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Costello syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012600, VCV000012603, VCV000012612, VCV000012613, VCV000040430, VCV000163690, VCV000180854, VCV000279921, VCV001209208, PM5_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012602, PS1_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The c.34G>A (p.G12S) alteration is located in exon 2 (coding exon 1) of the HRAS gene. This alteration results from a G to A substitution at nucleotide position 34, causing the glycine (G) at amino acid position 12 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration and several other alterations at the same codon (p.G12A, p.G12C, p.G12D, p.G12E, and p.G12V) have been reported in individuals with HRAS-related RASopathy including many de novo occurrences (Aoki, 2005; Hoornaert, 2006; Gripp, 2006; Lo, 2008; Burkitt-Wright, 2012). The p.G12S alteration is the most prevalent alteration reported in patients with HRAS-related RASopathy (reviewed in Wey, 2013). This amino acid position is highly conserved in available vertebrate species. The p.G12 amino acid is located within the phosphate-binding loop of the GTP-binding site (Gripp, 2006). Functional analysis demonstrated that protein products containing the p.G12S alteration have increased binding of GTP, resulting in increased amounts of the active form the HRAS protein (Wey, 2013). Additionally, patient cell lines with the p.G12S alteration were found to have reduced expression of C4ST-1 mRNA compared to wild type (Kluppel 2012), and in vivo studies showed abnormal neuronal cell proliferation and astrogenesis (Paquin, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The HRAS c.34G>A variant is predicted to result in the amino acid substitution p.Gly12Ser. This variant is one of the most frequent pathogenic variants in HRAS and has been documented as a de novo event in multiple unrelated individuals with Costello Syndrome (for examples see - Aoki et. al. 2005. PubMed ID: 17177115; Gripp et al. 2011. PubMed ID: 21834037). Additionally, different amino acid substitutions (p.Gly12Arg, p.Gly12Cys, p.Gly12Asp, p.Gly12Ala, p.Gly12Val) affecting the same amino acid have been reported as pathogenic (Human Gene Mutation Database). Functional studies demonstrate increased GTP-bound HRAS (active state) in cells transfected with the p.Gly12Ser variant, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Niihori et al. 2011. PubMed ID: 21850009). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted by multiple labs and the ClinGen RASopathy Variant Curation Expert Panel as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12602/). This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
HRAS-Related Costello Syndrome.	Adam MP	-	2023	PMID: 20301680
Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders.	Marinakis NM	American journal of medical genetics. Part A	2021	PMID: 34008892
Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group.	Li H	Journal of the National Cancer Institute	2021	PMID: 33372952
Costello syndrome: Clinical phenotype, genotype, and management guidelines.	Gripp KW	American journal of medical genetics. Part A	2019	PMID: 31222966
ClinGen's RASopathy Expert Panel consensus methods for variant interpretation.	Gelb BD	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29493581
Attenuated phenotype of Costello syndrome and early death in a patient with an HRAS mutation (c.179G>T; p.Gly60Val) affecting signalling dynamics.	Gripp KW	Clinical genetics	2017	PMID: 28139825
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.	Chang MT	Nature biotechnology	2016	PMID: 26619011
An attenuated phenotype of Costello syndrome in three unrelated individuals with a HRAS c.179G>A (p.Gly60Asp) mutation correlates with uncommon functional consequences.	Gripp KW	American journal of medical genetics. Part A	2015	PMID: 25914166
Somatic HRAS p.G12S mutation causes woolly hair and epidermal nevi.	Levinsohn JL	The Journal of investigative dermatology	2014	PMID: 24129065
Kinetic mechanisms of mutation-dependent Harvey Ras activation and their relevance for the development of Costello syndrome.	Wey M	Biochemistry	2013	PMID: 24224811
Craniofacial and dental malformations in Costello syndrome: A detailed evaluation using multi-detector row computed tomography.	Takahashi M	Congenital anomalies	2013	PMID: 23751039
Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.	Groesser L	Nature genetics	2012	PMID: 22683711
Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val.	Burkitt-Wright EM	American journal of medical genetics. Part A	2012	PMID: 22495892
C4ST-1/CHST11-controlled chondroitin sulfation interferes with oncogenic HRAS signaling in Costello syndrome.	Klüppel M	European journal of human genetics : EJHG	2012	PMID: 22317973
HRAS mutation mosaicism causing urothelial cancer and epidermal nevus.	Hafner C	The New England journal of medicine	2011	PMID: 22087699
HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome.	Niihori T	Journal of human genetics	2011	PMID: 21850009
Molecular confirmation of HRAS p.G12S in siblings with Costello syndrome.	Gripp KW	American journal of medical genetics. Part A	2011	PMID: 21834037
Costello syndrome with severe cutis laxa and mosaic HRAS G12S mutation.	Girisha KM	American journal of medical genetics. Part A	2010	PMID: 20979192
Enhanced human brain associative plasticity in Costello syndrome.	Dileone M	The Journal of physiology	2010	PMID: 20660566
Recurring G12S mutation of HRAS in a Chinese child with Costello syndrome with high alkaline phosphatase level.	Zhang H	Biochemical genetics	2009	PMID: 19669404
Costello syndrome H-Ras alleles regulate cortical development.	Paquin A	Developmental biology	2009	PMID: 19371735
Male-to-male transmission of Costello syndrome: G12S HRAS germline mutation inherited from a father with somatic mosaicism.	Sol-Church K	American journal of medical genetics. Part A	2009	PMID: 19206176
Partially correlated thin annular sources: the scalar case.	Gori F	Journal of the Optical Society of America. A, Optics, image science, and vision	2008	PMID: 18978862
Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype?	Gripp KW	American journal of medical genetics. Part A	2008	PMID: 18247425
Severe neonatal manifestations of Costello syndrome.	Lo IF	Journal of medical genetics	2008	PMID: 18039947
Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation.	van der Burgt I	Journal of medical genetics	2007	PMID: 17412879
Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.	Zampino G	Human mutation	2007	PMID: 17054105
Somatic mosaicism for an HRAS mutation causes Costello syndrome.	Gripp KW	American journal of medical genetics. Part A	2006	PMID: 16969868
Recurring HRAS mutation G12S in Dutch patients with Costello syndrome.	van Steensel MA	Experimental dermatology	2006	PMID: 16881968
Paternal bias in parental origin of HRAS mutations in Costello syndrome.	Sol-Church K	Human mutation	2006	PMID: 16835863
Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases.	Kerr B	Journal of medical genetics	2006	PMID: 16443854
HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.	Estep AL	American journal of medical genetics. Part A	2006	PMID: 16372351
HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.	Gripp KW	American journal of medical genetics. Part A	2006	PMID: 16329078
The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene.	Hoornaert KP	Journal of medical genetics	2006	PMID: 16155195
Germline mutations in HRAS proto-oncogene cause Costello syndrome.	Aoki Y	Nature genetics	2005	PMID: 16170316
Myopathy with muscle spindle excess: A new congenital neuromuscular syndrome?	Selcen D	Muscle & nerve	2001	PMID: 11150980
http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HRAS	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/51947641-2e77-498f-93d6-ca73b8e343de	-	-	-	-
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Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_005343.4(HRAS):c.34G>A (p.Gly12Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894229 ...