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

  • See Evidence submitted by expert panel for details.

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

CA122549

12602 (ClinVar)

Gene: LRRC56
Condition: Costello syndrome
Inheritance Mode: Autosomal dominant inheritance
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
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Pathogenic

Met criteria codes 7
PS4 PS3 PS2_Very Strong PP3 PP2 PM1 PM2

Evidence Links 15

Expert Panel

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.
Met criteria codes
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).

PS2_Very Strong
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)

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)

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