ClinVar Miner

Submissions for variant NM_002755.3(MAP2K1):c.370C>T (p.Pro124Ser) (rs1057519732)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV001250385 SCV001424740 pathogenic Rasopathy 2020-07-02 reviewed by expert panel curation 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.
GeneDx RCV000482718 SCV000572401 pathogenic not provided 2016-12-28 criteria provided, single submitter clinical testing The P124S variant in the MAP2K1 gene has not been reported previously as a germline pathogenic variant nor as a benign variant, to our knowledge. It is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P124S variant is a non-conservative amino acid substitution and occurs at a position that is conserved across species. Additionally, missense variants at the same codon (P124Q, P124L) and in a nearby residue (G128V) have been reported in the Human Gene Mutation Database in association with cardio-faciocutaneous syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore the P124S variant is considered to be pathogenic
Mendelics RCV000989347 SCV001139638 likely pathogenic Cardiofaciocutaneous syndrome 3 2019-05-28 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000433235 SCV000504542 pathogenic Cutaneous melanoma 2016-03-10 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444865 SCV000504543 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426713 SCV000504544 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433927 SCV000504545 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443916 SCV000504546 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000824936 SCV000965971 uncertain significance Noonan syndrome no assertion criteria provided clinical testing

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