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_004985.5(KRAS):c.40G>A (p.Val14Ile)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA156358

12589 (ClinVar)

Gene: KRAS

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

Approved on: 2024-12-03

Published on: 2025-03-31

HGVS expressions

NM_004985.5:c.40G>A

NM_004985.5(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

NG_007524.2:g.10659G>A

ENST00000556131.2:c.40G>A

ENST00000557334.6:c.40G>A

ENST00000685328.1:c.40G>A

ENST00000686877.1:c.40G>A

ENST00000686969.1:c.40G>A

ENST00000687356.1:c.40G>A

ENST00000688940.1:c.40G>A

ENST00000690804.1:c.40G>A

ENST00000692768.1:c.-88+5406G>A

ENST00000693229.1:c.40G>A

ENST00000256078.10:c.40G>A

ENST00000311936.8:c.40G>A

ENST00000256078.8:c.40G>A

ENST00000311936.7:c.40G>A

ENST00000556131.1:c.40G>A

ENST00000557334.5:c.40G>A

NM_004985.4:c.40G>A

NM_033360.3:c.40G>A

NM_001369786.1:c.40G>A

NM_001369787.1:c.40G>A

NM_033360.4:c.40G>A

Pathogenic

PS4 PS3_Moderate PP2 PP3 PM1 PS2_Very Strong PM2_Supporting

BA1 BS1 BS3 BP1 BP4

Evidence Links 5

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.40G>A variant in the KRAS gene is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 14 (p.Val14Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.803 supporting a deleterious impact to KRAS function (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). This variant resides within a region (amino acids 10-17) of KRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). This variant has been reported in 6 individuals with two confirmed de novo occurrences with clinical features of a RASopathy (PS4, PS2_VeryStrong; PMIDs: 16474405, 17704260, 18958496, 19020799, 20949621). In vitro functional studies showed that the p.Val14Ile variant enhanced RAS/MEK/ERK activation (PS3_Moderate; PMID: 20949621). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PS3_Moderate, PM1, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024)

PS4

The p.Val14Ile variant has been identified in at least 6 independent occurrences in patients with clinical features of a RASopathy (PMID: 20949621, 19020799, 18958496, 17704260, 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). PubMed:17704260

PS3_Moderate

In vitro functional studies showed that the p.Val14Ile variant enhanced RAS/MEK/ERK activation (PMID: 20949621).

Expression of the KRAS mutants in presence of serum leads to overall enhanced MEK1/2 phosphorylation and enhanced ERK1/2 phosphorylation. Pull-down experiments of GTP-bound KRAS proteins (RASGTP) showed that mutant increased GTP-bound level. PubMed:20949621

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).

PP3

The computational predictor REVEL gives a score of 0.803 supporting a deleterious impact to KRAS function

PM1

This variant resides within a region (amino acids 10-17) of KRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP

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).

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). PubMed:16474405

PM2_Supporting

This variant is absent from gnomAD v2.1.1

BA1

This variant is absent from gnomAD v2.1.1

BS1

This variant is absent from gnomAD v2.1.1

BS3

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

BP1

BP4

The computational predictor REVEL gives a score of 0.803 supporting a deleterious impact to KRAS function

Curation History

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