Variant: NM_002755.3(MAP2K1):c.370C>T (p.Pro124Ser)

CA16602456

375981 (ClinVar)

Gene: MAP2K1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 5725ca85-ac7d-4884-bdcb-d5ee4a24cee6

HGVS expressions

NM_002755.3:c.370C>T
NM_002755.3(MAP2K1):c.370C>T (p.Pro124Ser)
NM_002755.4:c.370C>T
ENST00000307102.9:c.370C>T
ENST00000425818.2:n.881C>T
NC_000015.10:g.66436824C>T
CM000677.2:g.66436824C>T
NC_000015.9:g.66729162C>T
CM000677.1:g.66729162C>T
NC_000015.8:g.64516216C>T
NG_008305.1:g.54952C>T

Pathogenic

• Met criteria codes: PS3 PP2 PP3 PS2_Very Strong PM2 PM1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.370C>T (p.Pro124Ser) variant in MAP2K1 has been observed as a de novo occurrence with maternity and paternity confirmed in 2 probands with features of a RASopathy (PS2_VeryStrong; GeneDx internal data, ClinVar SCV000572401.5). In vitro functional studies provide some evidence that the p.Pro124Ser variant may impact protein function (PS3; PMID: 22197931). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). The p.Pro124Ser 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). 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 MAP2K1 (PM1; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Leu92Arg 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, PS3, PM1, PM2, PP2, PP3.

Met criteria codes

• PS3: Compared to WT MAP2K1, the P124S variant caused increased phosphorylation of ERK1/2 in HEK293T cells. BRAFV600E was used as a positive control.
• PP2: MAP2K1 is a missense-constrained gene (PMID: 29493581).
• PP3: REVEL 0.855. Entirely conserved in UCSC database. Alamut does not predict an impact to splicing.
• PS2_Very Strong: Observed in 2 de novo cases with parental confirmation.
• PM2: Absent from both versions of gnomAD.
• PM1: Falls between amino acids 124 and 134 (PMID: 29493581).

Approved on: 2020-07-02

Published on: 2020-07-02