NM_005343.4(HRAS):c.37G>T (p.Gly13Cys) AND Noonan syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 3, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000678903.4

Allele description [Variation Report for NM_005343.4(HRAS):c.37G>T (p.Gly13Cys)]

NM_005343.4(HRAS):c.37G>T (p.Gly13Cys)

Genes:

HRAS:HRas proto-oncogene, GTPase [Gene - OMIM - HGNC]
LRRC56:leucine rich repeat containing 56 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_005343.4(HRAS):c.37G>T (p.Gly13Cys)

Other names:

p.G13C:GGT>TGT; NM_005343.3(HRAS):c.37G>T

HGVS:

NC_000011.10:g.534286C>A
NG_007666.1:g.6265G>T
NM_001130442.3:c.37G>T
NM_001318054.2:c.-283G>T
NM_005343.4:c.37G>TMANE SELECT
NM_176795.5:c.37G>T
NP_001123914.1:p.Gly13Cys
NP_005334.1:p.Gly13Cys
NP_789765.1:p.Gly13Cys
LRG_506t1:c.37G>T
LRG_506:g.6265G>T
LRG_506p1:p.Gly13Cys
NC_000011.9:g.534286C>A
NM_005343.2:c.37G>T
NM_005343.3:c.37G>T
P01112:p.Gly13Cys
c.37G>T

Protein change:

G13C; GLY13CYS

Links:

UniProtKB: P01112#VAR_026107; OMIM: 190020.0007; dbSNP: rs104894228

NCBI 1000 Genomes Browser:

rs104894228

Molecular consequence:

NM_001318054.2:c.-283G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001130442.3:c.37G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005343.4:c.37G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_176795.5:c.37G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Noonan syndrome (NS)
Synonyms:: Noonan's syndrome; Pseudo-Turner syndrome
Identifiers:: MONDO: MONDO:0018997; MeSH: D009634; MedGen: C0028326; OMIM: PS163950

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000616363	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Pathogenic (Apr 3, 2017)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 16329078, 21438134, 29493581 Citation Link,
SCV000805106	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	no assertion criteria provided	Pathogenic (Aug 24, 2017)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000616363

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Pathogenic
(Apr 3, 2017)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000805106

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

no assertion criteria provided

Pathogenic
(Aug 24, 2017)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.

Gripp KW, Lin AE, Stabley DL, Nicholson L, Scott CI Jr, Doyle D, Aoki Y, Matsubara Y, Zackai EH, Lapunzina P, Gonzalez-Meneses A, Holbrook J, Agresta CA, Gonzalez IL, Sol-Church K.

Am J Med Genet A. 2006 Jan 1;140(1):1-7.

PubMed [citation]

PMID:: 16329078

Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C.

Gripp KW, Hopkins E, Sol-Church K, Stabley DL, Axelrad ME, Doyle D, Dobyns WB, Hudson C, Johnson J, Tenconi R, Graham GE, Sousa AB, Heller R, Piccione M, Corsello G, Herman GE, Tartaglia M, Lin AE.

Am J Med Genet A. 2011 Apr;155A(4):706-16. doi: 10.1002/ajmg.a.33884. Epub 2011 Mar 15.

PubMed [citation]

PMID:: 21438134
PMCID:: PMC4166651

See all PubMed Citations (3)

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616363.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

The c.37G>T (p.Gly13Cys) 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 21438134, 16329078). The p.Gly13Cys variant has been identified in at least 3 other independent occurrence in patients with clinical features of a RASopathy (PS4_Moderate; PMID: 16372351). 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). Computational prediction tools and conservation analysis suggest that the p.Gly13Cys 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). 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): PP2, PP3, PM1, PM2, PS4_Moderate, PS2_VeryStrong.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital, SCV000805106.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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