Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_005343.3(HRAS):c.37G>T (p.Gly13Cys)

Curation History

CA295247

12606 (ClinVar)

Gene: LRRC56

Condition: Noonan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 77fd6395-3146-46f0-86ca-08fb626eb660

Approved on: 2017-04-03

Published on: 2018-12-10

HGVS expressions

NM_005343.3:c.37G>T

NM_005343.3(HRAS):c.37G>T (p.Gly13Cys)

NM_001130442.1:c.37G>T

NM_005343.2:c.37G>T

NM_176795.3:c.37G>T

NM_001130442.2:c.37G>T

NM_001318054.1:c.-283G>T

NM_176795.4:c.37G>T

NM_005343.4:c.37G>T

ENST00000311189.7:c.37G>T

ENST00000397594.5:c.37G>T

ENST00000397596.6:c.37G>T

ENST00000417302.5:c.37G>T

ENST00000451590.5:c.37G>T

ENST00000468682.2:n.525G>T

ENST00000482021.1:n.160G>T

ENST00000493230.5:c.37G>T

NC_000011.10:g.534286C>A

CM000673.2:g.534286C>A

NC_000011.9:g.534286C>A

CM000673.1:g.534286C>A

NC_000011.8:g.524286C>A

NG_007666.1:g.6265G>T

Pathogenic

PM2 PM1 PP3 PP2 PS4_Moderate PS2_Very Strong

Evidence Links 3

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

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.

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

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). PubMed:29493581

PP3

Computational prediction tools and conservation analysis suggest that the p.Gly13Cys variant may impact the protein (PP3).

PP2

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).

PS4_Moderate

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).

PS2_Very Strong

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).

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.