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Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

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Criteria Specification: CSpec Registry PDF

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

CA156358

12589 (ClinVar)

Gene: KRAS
Condition: Noonan syndrome
Inheritance Mode: Autosomal dominant inheritance

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

Met criteria codes 6
PM1 PS2_Very Strong PS3 PS4_Moderate PP3 PP2

Expert Panel

Evidence Links 6

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).
Met criteria codes
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).

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).

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

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).

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).
Approved on: 2017-04-03
Published on: 2018-12-10
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