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_004985.4(KRAS):c.65A>G (p.Gln22Arg)

Curation History

CA235299

40452 (ClinVar)

Gene: KRAS

Condition: Noonan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: f148a4b1-945e-4dc1-8d90-77bc00006052

Approved on: 2017-04-03

Published on: 2018-12-10

HGVS expressions

NM_004985.4:c.65A>G

NM_004985.4(KRAS):c.65A>G (p.Gln22Arg)

NC_000012.12:g.25245320T>C

CM000674.2:g.25245320T>C

NC_000012.11:g.25398254T>C

CM000674.1:g.25398254T>C

NC_000012.10:g.25289521T>C

NG_007524.1:g.10601A>G

NM_033360.3:c.65A>G

ENST00000256078.8:c.65A>G

ENST00000311936.7:c.65A>G

ENST00000556131.1:c.65A>G

ENST00000557334.5:c.65A>G

Pathogenic

PM2 PM6_Strong PS4_Moderate PS3 PP3 PP2

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.65A>G (p.Gln22Arg) variant in KRAS has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; Partners LMM internal data; GTR ID 21766; ClinVar SCV000198473.4). In vitro functional studies provide some evidence that the p.Gln22Arg variant may impact protein function (PS3; PMID 20652921). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The p.Gln22Arg variant has been identified in 2 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré hospital; GTR ID: 26957, 21766, 506381, 28338; ClinVar SCV000198473.4; SCV000207881.8; SCV000253709.2; SCV000207633.1). Computational prediction tools and conservation analysis suggest that the p.Gln22Arg variant may impact the protein (PP3). The variant is located in the KRAS 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): PM6_Strong, PS3, PM2, PS4_Moderate, PP2, PP3.

PM2

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

PM6_Strong

PS4_Moderate

The p.Gln22Arg variant has been identified in 2 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré hospital; GTR ID: 26957, 21766, 506381, 28338; ClinVar SCV000198473.4; SCV000207881.8; SCV000253709.2; SCV000207633.1).

PS3

In vitro functional studies provide some evidence that the p.Gln22Arg variant may impact protein function (PS3; PMID 20652921).

PP3

Computational prediction tools and conservation analysis suggest that the p.Gln22Arg variant may impact the protein (PP3).

PP2

The variant is located in the KRAS 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).

Curation History

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