Variant: NM_002755.4(MAP2K1):c.275T>G (p.Leu92Arg)

CA134601

44588 (ClinVar)

Gene: MAP2K1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 2986f8eb-3ee8-416d-a279-f72ff1c134a1

Approved on: 2024-09-17

Published on: 2024-10-01

HGVS expressions

NM_002755.4:c.275T>G
NM_002755.4(MAP2K1):c.275T>G (p.Leu92Arg)
NC_000015.10:g.66435221T>G
CM000677.2:g.66435221T>G
NC_000015.9:g.66727559T>G
CM000677.1:g.66727559T>G
NC_000015.8:g.64514613T>G
NG_008305.1:g.53349T>G
ENST00000684779.1:c.209T>G
ENST00000685172.1:c.275T>G
ENST00000685763.1:c.275T>G
ENST00000686347.1:c.275T>G
ENST00000687191.1:n.711T>G
ENST00000689951.1:c.275T>G
ENST00000691077.1:c.275T>G
ENST00000691576.1:c.275T>G
ENST00000691937.1:c.275T>G
ENST00000692487.1:c.275T>G
ENST00000692683.1:c.209T>G
ENST00000693150.1:c.209T>G
ENST00000307102.10:c.275T>G
ENST00000307102.9:c.275T>G
ENST00000425818.2:n.786T>G
NM_002755.3:c.275T>G

Pathogenic

• Met criteria codes: PS4_Moderate PP2 PP3 PM6_Very Strong PM2_Supporting

• Not Met criteria codes: BA1 BS1 BP4

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K1 Version 2.1.0

Evidence submitted by expert panel

RASopathy VCEP

The c.275T>G variant in the MAP2K1 gene is a missense variant predicted to cause substitution of leucine by arginine at amino acid 92 (p.Leu92Arg). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.793 (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). This variant has been reported in 4 independent patients with clinical feature of a RASopathy, 1 as a confirmed de novo occurrence and 2 as unconfirmed de novo occurrences (PS4_Moderate, PM6_VeryStrong; GeneDx, APHP-Robert Debré hospital, Laboratory for Molecular Medicine internal data; ClinVar SCV000207940.11, SCV000965969.1, SCV000061251.5, 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: PM6_VeryStrong, PS4_Moderate, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 09/17/2024)

Met criteria codes

• PS4_Moderate: Reported in at least 4 independent patients diagnosed with a RASopathy. 3 were de novo occurrences, including 1 case with parental confirmation (PS4_Moderate; PMID: 35524774, GeneDx, APHP-Robert Debré hospital, Laboratory for Molecular Medicine internal data; ClinVar SCV000207940.11, SCV000965969.1, SCV000061251.5).
• 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).
• PP3: The computational predictor REVEL gives a score of 0.793 (PP3).
• PM6_Very Strong: Reported in at least 3 de novo occurrences, including 1 case with parental confirmation, in patients diagnosed with a RASopathy (PS2_VeryStrong; GeneDx, APHP-Robert Debré hospital, Laboratory for Molecular Medicine internal data; ClinVar SCV000207940.11, SCV000965969.1, SCV000061251.5).
• PM2_Supporting: This variant was absent from gnomAD v4.1.0.

Not Met criteria codes

• BA1: This variant was absent from gnomAD v4.1.0.
• BS1: This variant was absent from gnomAD v4.1.0.
• BP4: The computational predictor REVEL gives a score of 0.793 (PP3).