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.34G>A (p.Gly12Ser)

Curation History

CA122549

12602 (ClinVar)

Gene: LRRC56

Condition: Costello syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 51947641-2e77-498f-93d6-ca73b8e343de

Approved on: 2017-04-03

Published on: 2018-12-10

HGVS expressions

NM_005343.3:c.34G>A

NM_005343.3(HRAS):c.34G>A (p.Gly12Ser)

NC_000011.10:g.534289C>T

CM000673.2:g.534289C>T

NC_000011.9:g.534289C>T

CM000673.1:g.534289C>T

NC_000011.8:g.524289C>T

NG_007666.1:g.6262G>A

NM_001130442.1:c.34G>A

NM_005343.2:c.34G>A

NM_176795.3:c.34G>A

NM_001130442.2:c.34G>A

NM_001318054.1:c.-286G>A

NM_176795.4:c.34G>A

NM_005343.4:c.34G>A

ENST00000311189.7:c.34G>A

ENST00000397594.5:c.34G>A

ENST00000397596.6:c.34G>A

ENST00000417302.5:c.34G>A

ENST00000451590.5:c.34G>A

ENST00000468682.2:n.522G>A

ENST00000482021.1:n.157G>A

ENST00000493230.5:c.34G>A

Pathogenic

PS2_Very Strong PS4 PS3 PP3 PP2 PM1 PM2

Evidence Links 15

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

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.

PS2_Very Strong

PS4

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).

PS3

In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact protein function (PS3; PMID: 17412879).

In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact protein function (PS3; PMID: 17412879). PubMed:17412879

PP3

Computational prediction tools and conservation analysis suggest that the p.Gly12Ser 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).

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)

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

PM2

This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org).

Curation History

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