ClinVar Miner

Submissions for variant NM_002755.4(MAP2K1):c.364A>G (p.Asn122Asp) (rs876657651)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000220187 SCV001335321 pathogenic Rasopathy 2020-03-16 reviewed by expert panel curation The c.364A>G (p.Asn122Asp) variant in MAP2K1 was absent from gnomAD (PM2). It has been observed in 3 probands with clinical features of a RASopathy, including 1 de novo occurrence with maternity and paternity confirmed and 2 assumed de novo occurrences (PM2_VS; SCV000271240.2; Otto-von-Guericke-Universität Magdeburg internal communication; Invitae internal data, SCV000947966.1). Of these patients, 2 received a clinical diagnosis of either Noonan syndrome or cardiofaciocutaneous syndrome (PS4_Supporting). Of note, this variant was observed in 1 proband without clinical information who inherited it from a parent with unknown clinical status (GeneDx internal data). The c.364A>G (p.Asm122Asp) variant is located in MAP2K1, 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). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy based on RASopathy-specific ACMG/AMP criteria (PMID:29493581): PS2_VS, PS4_Supporting, PM2, PP2.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844674 SCV000271240 likely pathogenic Noonan syndrome 2015-07-28 criteria provided, single submitter clinical testing The p.Asn122Asp variant in MAP2K1 has been identified by our laboratory as a de novo occurrence in 1 individual with clinical features of Noonan syndrome. It wa s absent from large population studies. Computational prediction tools and conse rvation analysis suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Asn122Asp variant is likely pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763361 SCV000894052 likely pathogenic Noonan syndrome 1; Cardiofaciocutaneous syndrome 3 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000220187 SCV000947966 uncertain significance Rasopathy 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 122 of the MAP2K1 protein (p.Asn122Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MAP2K1-related conditions. ClinVar contains an entry for this variant (Variation ID: 228273). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
MNM Diagnostics RCV001312196 SCV001502658 pathogenic Cardiofaciocutaneous syndrome 3 2020-02-10 criteria provided, single submitter clinical testing According to ACMG Guidelines, the variant meets the following criteria of pathogenicity: PS2, PS4, PM2, PP2, PP3, PP4. This is a de novo variant of a missense heterozygotic mutation in exon 3 of MAP2K1 gene in position c.364A>G. The change results in the asparagine to aspartate substitution in codon 122. MAP2K1 mutations are responsible for the Cardio-facio-cutaneous Syndrome type 3 (CFCS) observed as well in the proband.

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