Variant: NM_002755.4(MAP2K1):c.169A>C (p.Lys57Gln)

CA134595

40779 (ClinVar)

Gene: MAP2K1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 5fa3b275-1dad-4c57-bed5-dd904a8b11bb

Approved on: 2024-12-03

Published on: 2025-03-27

HGVS expressions

NM_002755.4:c.169A>C
NM_002755.4(MAP2K1):c.169A>C (p.Lys57Gln)
NC_000015.10:g.66435115A>C
CM000677.2:g.66435115A>C
NC_000015.9:g.66727453A>C
CM000677.1:g.66727453A>C
NC_000015.8:g.64514507A>C
NG_008305.1:g.53243A>C
ENST00000684779.1:c.103A>C
ENST00000685172.1:c.169A>C
ENST00000685763.1:c.169A>C
ENST00000686347.1:c.169A>C
ENST00000687191.1:n.605A>C
ENST00000689951.1:c.169A>C
ENST00000691077.1:c.169A>C
ENST00000691576.1:c.169A>C
ENST00000691937.1:c.169A>C
ENST00000692487.1:c.169A>C
ENST00000692683.1:c.103A>C
ENST00000693150.1:c.103A>C
ENST00000307102.10:c.169A>C
ENST00000307102.9:c.169A>C
ENST00000425818.2:n.680A>C
NM_002755.3:c.169A>C

Pathogenic

• Met criteria codes: PP2 PP3 PM1 PM2 PM6 PS4 PS2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K1 Version 2.3.0

Evidence submitted by expert panel

RASopathy VCEP

The c.169A>C variant in the MAP2K1 gene is a missense variant predicted to cause substitution of lysine by glutamine at amino acid 57 (p.Lys57Gln). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.726, evidence that the p.Lys57Gln variant may impact the protein function (PP3). The variant is located in the MAP2K1 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). The variant is located in a specific region supporting pathogenicity (PM1, aa 43-61). This variant has been reported in at least 6 independent patients with clinical feature of a RASopathy, 1 as a confirmed de novo occurrence and 1 as an unconfirmed de novo occurrence (PS2, PS4; Partners LMM, GeneDx, Invitae, Baylor, Otto von Guericke University Magdeburg internal data; ClinVar SCV000061249.5, SCV000207949.3, SCV001568953.4, PMID: 35524774). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2, PS4, PM1, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024)

Met criteria codes

• PP2: The variant is located in the MAP2K1 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).
• PP3: Computational prediction tools and conservation analysis suggest that the p.Lys57Gln variant may impact the protein (PP3)
• PM1: The variant is located in a specific region supporting pathogenicity (aa 43-61).
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: This variant has been reported in at least 6 independent patients with clinical feature of a RASopathy (Partners LMM, GeneDx, Invitae, Baylor, Otto von Guericke University Magdeburg internal data; ClinVar SCV000061249.5, SCV000207949.3, SCV001568953.4, PMID: 35524774)
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline