ClinVar Miner

Submissions for variant NM_030662.3(MAP2K2):c.170T>G (p.Phe57Cys) (rs121434497)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000208756 SCV000616538 pathogenic Cardio-facio-cutaneous syndrome 2017-05-09 reviewed by expert panel curation The c.170T>G (p.Phe57Cys) variant in MAP2K2 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 16439621). In vitro functional studies provide some evidence that the p.Phe57Cys variant may impact protein function (PS3; PMID 16439621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). A different pathogenic missense variant has been previously identified at this codon of MAP2K2 (p.Phe57Val for malignant melanoma) which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 8273). The variant is located in the MAP2K2 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 MAP2K2 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe57Cys 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): PM6, PS3, PM2, PM5, PP2, PM1, PP3.
GeneDx RCV000158038 SCV000207973 pathogenic not provided 2016-04-22 criteria provided, single submitter clinical testing p.Phe57Cys (TTT>TGT): c.170 T>G in exon 2 of the MAP2K2 gene (NM_030662.3).The F57C mutation in the MAP2K2 gene has been reported previously in association with CFC syndrome (Rodriguez-Viciana P et al., 2006). Functional in vitro studies have demonstrated that the F57C mutation results in increased kinase activity and activation of downstream effectors (MEK and ERK) (Rodriguez-Viciana P et al., 2008). The F57C mutation 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 highly conserved across species. Moreover, mutations in this residue (F57I, F57V, F57L) and in nearby residues (K61E, K61T, A62P) have been reported in association with CFC syndrome, further supporting the functional importance of this region of the protein. Furthermore, the F57C mutation was not observed inapproximately 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. In summary, F57C in the MAP2K2 gene is interpreted as a disease-causing mutation.The variant is found in CARDIOMYOPATHY panel(s).
GeneReviews RCV000208756 SCV000264641 pathogenic Cardio-facio-cutaneous syndrome 2016-03-03 no assertion criteria provided literature only
OMIM RCV000008761 SCV000028970 pathogenic Cardiofaciocutaneous syndrome 4 2008-02-01 no assertion criteria provided literature only

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