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]

Link to SEPIO compliant JSON-LD document

Variant: NM_004985.4(KRAS):c.178G>C (p.Gly60Arg)

CA273416

12586 (ClinVar)

Gene: KRAS

Condition: cardiofaciocutaneous syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: a8c6153e-d737-4b86-8d68-caf8ddd418fd

HGVS expressions

NM_004985.4:c.178G>C

NM_004985.4(KRAS):c.178G>C (p.Gly60Arg)

NC_000012.12:g.25227346C>G

CM000674.2:g.25227346C>G

NC_000012.11:g.25380280C>G

CM000674.1:g.25380280C>G

NC_000012.10:g.25271547C>G

NG_007524.1:g.28575G>C

NM_033360.3:c.178G>C

ENST00000256078.8:c.178G>C

ENST00000311936.7:c.178G>C

ENST00000557334.5:c.112-17435G>C

Pathogenic

PM6_Strong PS3 PM2 PM1 PP3 PP2

Evidence Links 2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.178G>C (p.Gly60Arg) variant in KRAS has been reported in the literature as a de novo occurrence in 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 16474404, 20949621). In vitro functional studies provide some evidence that the p.Gly60Arg variant may impact protein function (PS3; PMID 20949621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in KRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; 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 KRAS (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly60Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PS3, PM2, PM1, PP3, PP2.

PM6_Strong

The c.178G>C (p.Gly60Arg) variant in KRAS has been reported in the literature as a de novo occurrence in 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 16474404, 20949621).

PS3

In vitro functional studies provide some evidence that the p.Gly60Arg variant may impact protein function (PS3; PMID 20949621).

In vitro functional studies provide some evidence that the p.Gly60Arg variant may impact protein function (PS3; PMID 20949621). PubMed:20949621

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 KRAS (PM1; PMID 29493581).

PP3

Computational prediction tools and conservation analysis suggest that the p.Gly60Arg variant may impact the protein (PP3).

PP2

The variant is in KRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581)

Approved on: 2017-04-03

Published on: 2018-12-10

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