MAP2K1 p.Phe53Ser

The c.158T>C variant in the MAP2K1 gene is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 53 (p.Phe53Ser). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.938 (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). Furthermore, the variant is in a location, analogous to MEK2 F57 residue, that has been defined by the ClinGen RASopathy Expert Panel functional domain of MAP2K1 (PM1). This variant has been reported in the literature in 4 individuals with clinical features of RASopathy with 1 unconfirmed de novo occurrence (PS4_Moderate, PM6_Supporting; PMIDs: 16439621, 18039235, 21062266, 30141192). ERK/MAPK phosphorylation assays showed that this variant led to significantly increased phosphorylation compared to wildtype (PS3_Moderate; PMID: 16439621, 17981815). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS3_Moderate, PS4_Moderate, PM1, PM2_Supporting, PM6_Supporting, PP2, PP3 (Specification Version 2.1, 9/17/2024)