ClinVar Genomic variation as it relates to human health

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)

The F53S variant in the MAP2K1 gene has been published previously as de novo in a patient with cardio-facio-cutaneous syndrome (Rodriguez-Viciana et al., 2006). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. F53S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies have shown that F53S results in increased phosphorylation of ERK (Rodriguez-Viciana et al., 2008). Additionally, the F53 residue is analagous to the F57 residue in MEK2, which is a known hotspot for variants (Rodriguez-Viciana et al., 2008). Therefore, we consider this variant to be pathogenic.

Variant summary: MAP2K1 c.158T>C (p.Phe53Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251374 control chromosomes. c.158T>C has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (example, Rodrigues-Viciana_2006, Yoon_2007, Siegel_2011, Bessis_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in significant stimulation of ERK phosphorylation relative to the wild-type control (example, Rodriguez-Viciana_2008). One clinical diagnostic laboratory and an expert panel (ClinGen RASopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.