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.40G>A (p.Val14Ile)

CA156358

12589 (ClinVar)

Gene: KRAS

Condition: Noonan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e103be05-5fbf-42b0-b4a8-809da2f2181d

HGVS expressions

NM_004985.4:c.40G>A

NM_004985.4(KRAS):c.40G>A (p.Val14Ile)

NC_000012.12:g.25245345C>T

CM000674.2:g.25245345C>T

NC_000012.11:g.25398279C>T

CM000674.1:g.25398279C>T

NC_000012.10:g.25289546C>T

NG_007524.1:g.10576G>A

NM_033360.3:c.40G>A

ENST00000256078.8:c.40G>A

ENST00000311936.7:c.40G>A

ENST00000556131.1:c.40G>A

ENST00000557334.5:c.40G>A

Pathogenic

PS3 PP3 PP2 PM1 PS2_Very Strong PS4_Moderate

Evidence Links 6

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.40G>A (p.Val14Ile) variant in KRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 16474405). The p.Val14Ile variant has been identified in at least 4 independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; PMID: 20949621, 19020799, 18958496, 17704260). In vitro functional studies provide some evidence that the p.Val14Ile variant may impact protein function (PS3; PMID: 20949621). 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). 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). Computational prediction tools and conservation analysis suggest that the p.Val14Ile variant may impact the protein (PP3). 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_Moderate, PS3, PM1, PP2, PP3).

PS3

In vitro functional studies provide some evidence that the p.Val14Ile variant may impact protein function (PS3; PMID: 20949621).

In vitro functional studies provide some evidence that the p.Val14Ile variant may impact protein function (PS3; PMID: 20949621). PubMed:20949621

PP3

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

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).

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).

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). PubMed:29493581

PS2_Very Strong

The c.40G>A (p.Val14Ile) variant in KRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 16474405).

PS4_Moderate

The p.Val14Ile variant has been identified in at least 4 independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; PMID: 20949621, 19020799, 18958496, 17704260).

The p.Val14Ile variant has been identified in at least 4 independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; PMID: 20949621, 19020799, 18958496, 17704260). PubMed:19020799

Approved on: 2017-04-03

Published on: 2018-12-10

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