ClinVar Miner

Submissions for variant NM_002755.3(MAP2K1):c.275T>G (p.Leu92Arg) (rs397516791)

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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 RCV000522848 SCV000616534 likely pathogenic Cardio-facio-cutaneous syndrome 2017-05-09 reviewed by expert panel curation The c.275T>G p.Leu92Arg variant in MAP2K1 has been reported in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, APHP-Robert Debré hospital internal data, GTR ID: 28338, 26957; ClinVar SCV000061251.5, SCV000207940.10). The p.Leu92Arg variant has been identified in an independent occurrencee in a patient with a RASopathy (PS4_Supporting; Partners LMM, GeneDx internal data, GTR ID: 21766, 26957 ClinVar SCV000061251.5 SCV000207940.10). This variant was absent from large population studies (PM2; ExAC, 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; 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 likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4_Supporting, PM2, PP3, PP2.
GeneDx RCV000158005 SCV000207940 likely pathogenic not provided 2017-01-13 criteria provided, single submitter clinical testing A novel L92R variant that is likely pathogenic was identified in the MAP2K1 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It has, however, been observed to be inherited in an apparently de novo manner in two patients tested at GeneDx. 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. L92R 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; however, in in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000522848 SCV000061251 likely pathogenic Cardio-facio-cutaneous syndrome 2019-02-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000522848 SCV000965969 likely pathogenic Cardio-facio-cutaneous syndrome no assertion criteria provided clinical testing

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