VCV000180856.13 - ClinVar

NM_005343.4(HRAS):c.506G>A (p.Arg169Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005343.4(HRAS):c.506G>A (p.Arg169Gln)

Variation ID: 180856 Accession: VCV000180856.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.5 11: 532700 (GRCh38) [ NCBI UCSC ] 11: 532700 (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	Sep 26, 2017	Feb 28, 2024	Oct 14, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005343.4:c.506G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005334.1:p.Arg169Gln	missense
NM_176795.5:c.*75G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_001130442.3:c.506G>A	NP_001123914.1:p.Arg169Gln	missense
NM_001318054.2:c.269G>A	NP_001304983.1:p.Arg90Gln	missense
NC_000011.10:g.532700C>T
NC_000011.9:g.532700C>T
NG_007666.1:g.7851G>A
LRG_506:g.7851G>A
LRG_506t1:c.506G>A	LRG_506p1:p.Arg169Gln

... more HGVS ... less HGVS

Protein change

R169Q, R90Q

Other names

Canonical SPDI

NC_000011.10:532699: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.

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00005

The Genome Aggregation Database (gnomAD) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

ClinGen: CA296075 dbSNP: rs142218590 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	723
LRRC56		-	-	GRCh38 GRCh38 GRCh37	346	1057

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.
Costello syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 14, 2023	RCV000463046.10
not provided	Uncertain significance (1)	criteria provided, single submitter	Jun 5, 2017	RCV000505776.1
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Jan 10, 2022	RCV002258816.2
Costello syndrome Epidermal nevus Large congenital melanocytic nevus Linear nevus sebaceous syndrome Malignant tumor of urinary bladder Thyroid cancer, nonmedullary, 2	Uncertain significance (1)	criteria provided, single submitter	Sep 28, 2021	RCV002492617.1
HRAS-related disorder	Uncertain significance (1)	criteria provided, single submitter	Feb 16, 2023	RCV003390855.4

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.
Uncertain significance (Jun 05, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000207863.6 First in ClinVar: Feb 24, 2015 Last updated: Sep 26, 2017	Comment: The R169Q variant has not been published in association with the Noonan syndrome spectrum to our knowledge; the variant has been observed as a germline … (more) The R169Q variant has not been published in association with the Noonan syndrome spectrum to our knowledge; the variant has been observed as a germline variant in an individual with lung cancer but no reported other phenotype (Marks et al., 2007). It was observed to co-occur with the M269T pathogenic variant in the SOS1 gene in a patient at GeneDx. The variant is observed in 1/10172 (0.01%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). R169Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. (less)
Uncertain significance (Jul 31, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: yes Allele origin: maternal	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001481324.2 First in ClinVar: Feb 27, 2021 Last updated: Feb 27, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Oct 14, 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: SCV000550344.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 28492532‚ 25742471 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the HRAS protein (p.Arg169Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the HRAS protein (p.Arg169Gln). This variant is present in population databases (rs142218590, gnomAD 0.01%). This missense change has been observed in individual(s) with an unspecified cancer (PMID: 25742471). ClinVar contains an entry for this variant (Variation ID: 180856). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Sep 28, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Malignant tumor of urinary bladder Large congenital melanocytic nevus Epidermal nevus Linear nevus sebaceous syndrome Thyroid cancer, nonmedullary, 2 Costello syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002800805.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Jan 10, 2022)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002537986.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: To the best of our knowledge, the HRAS c.506G>A (p.R169Q) variant has not been reported in individuals with HRAS-related disease. It was observed in 8/280666 … (more) To the best of our knowledge, the HRAS c.506G>A (p.R169Q) variant has not been reported in individuals with HRAS-related disease. It was observed in 8/280666 chromosomes among all subpopulations in the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 180856). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
Uncertain significance (Feb 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	HRAS-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004119909.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The HRAS c.506G>A variant is predicted to result in the amino acid substitution p.Arg169Gln. To our knowledge, this variant has not been reported in the … (more) The HRAS c.506G>A variant is predicted to result in the amino acid substitution p.Arg169Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-532700-C-T) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/180856/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

The R169Q variant has not been published in association with the Noonan syndrome spectrum to our knowledge; the variant has been observed as a germline variant in an individual with lung cancer but no reported other phenotype (Marks et al., 2007). It was observed to co-occur with the M269T pathogenic variant in the SOS1 gene in a patient at GeneDx. The variant is observed in 1/10172 (0.01%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). R169Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the HRAS protein (p.Arg169Gln). This variant is present in population databases (rs142218590, gnomAD 0.01%). This missense change has been observed in individual(s) with an unspecified cancer (PMID: 25742471). ClinVar contains an entry for this variant (Variation ID: 180856). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The HRAS c.506G>A variant is predicted to result in the amino acid substitution p.Arg169Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-532700-C-T) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/180856/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Assessing the clinical value of targeted massively parallel sequencing in a longitudinal, prospective population-based study of cancer patients.	Wong SQ	British journal of cancer	2015	PMID: 25742471

Text-mined citations for rs142218590 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_005343.4(HRAS):c.506G>A (p.Arg169Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs142218590 ...