ClinVar Miner

Submissions for variant NM_030662.3(MAP2K2):c.383C>A (p.Pro128Gln) (rs267607230)

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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 RCV000208770 SCV000616540 pathogenic Cardio-facio-cutaneous syndrome 2017-05-09 reviewed by expert panel curation The c.383C>A (p.Pro128Gln) variant in MAP2K2 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_Strong; 20358587). In vitro functional studies provide some evidence that the p.Pro128Gln variant may impact protein function (PS3; PMID 20358587). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). Computational prediction tools and conservation analysis suggest that the p.Pro128Gln variant may impact the protein (PP3). 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). 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): PP1_Strong, PS3, PM1, PM2, PP2, PP3.
GeneDx RCV000158021 SCV000207956 pathogenic not provided 2013-05-27 criteria provided, single submitter clinical testing p.Pro128Gln (CCG>CAG): c.383 C>A in exon 3 of the MAP2K2 gene (NM_030662.3). The P128Q missense mutation in the MAP2K2 gene has been reported previously in association with cardio-facio-cutaneous (CFC) syndrome (Rauen et al., 2009). Additionally, another mutation at the same codon (P128R) has been reported in association with CFC syndrome (Narumi et al., 2007). The variant is found in NOONAN panel(s).
GeneReviews RCV000208770 SCV000264642 pathogenic Cardio-facio-cutaneous syndrome 2016-03-03 no assertion criteria provided literature only
OMIM RCV000008764 SCV000028973 pathogenic Cardiofaciocutaneous syndrome 4 2010-04-01 no assertion criteria provided literature only

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