ClinVar Miner

Submissions for variant NM_030662.4(MAP2K2):c.619G>A (p.Glu207Lys) (rs727504382)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000524055 SCV000616543 likely pathogenic Cardio-facio-cutaneous syndrome 2017-05-09 reviewed by expert panel curation The c.619G>A (p.Glu207Lys) variant in MAP2K2 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; LMM GeneDx internal data; GTR ID's 21766, 26957; SCV000207959.10, SCV000204213.4). The p.Glu207Lys variant has been identified in 2 independent occurrences in patients with a RASopathy (PS4_Supporting; LMM GeneDx internal data; GTR ID's 21766, 26957; SCV000207959.10, SCV000204213.4). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Glu207Lys variant may impact the protein (PP3). 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). 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844675 SCV000204213 likely pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2013-12-23 criteria provided, single submitter clinical testing The Glu207Lys variant in MAP2K2 has been identified by our laboratory in 2 indiv iduals with clinical features of Noonan syndrome and Cardio-facio-cutaneous synd rome. This variant was found to have occurred de novo in one proband (LMM unpubl ished data). In addition, this variant is absent in large population studies. Co mputational analyses (biochemical amino acid properties, conservation, AlignGVGD , PolyPhen2, and SIFT) suggest that the Glu207Lys variant may impact the protein . In summary, this variant is likely pathogenic, though additional studies are r equired to fully establish its clinical significance.
GeneDx RCV000254662 SCV000207959 pathogenic not provided 2017-01-13 criteria provided, single submitter clinical testing The E207K missense variant has been observed apparently de novo in two probands tested internally and one additional proband from an external clinical laboratory (ClinVar: SCV000204213.2; Landrum et al. 2014) with clinical features or a diagnosis consistent with a RASopathy. In addition, it has also been published as a somatic variant identified in malignant melanomas (Nikolaev et al., 2012). The E207K 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. The E207K variant 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. The E207K variant in the MAP2K2 gene is analogous to another pathogenic variant, E203K, seen in the MAP2K1 gene. In vitro functional studies of this analogous MAP2K1 E203K variant demonstrated that it results in increased phosphorylation of ERK1 and ERK2 in comparison to wild-type (Delaney et al., 2002). Thus, given the homology of these two genes in both structure and function, we can conclude that the E207K variant in the MAP2K2 gene would also have a similar gain-of-function effect in the RAS/MAPK pathway. Therefore, this variant is pathogenic.
Invitae RCV000158024 SCV000815593 likely pathogenic Rasopathy 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 207 of the MAP2K2 protein (p.Glu207Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual with features consistent with a RASopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 40813). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Blueprint Genetics RCV000254662 SCV000927266 pathogenic not provided 2017-05-16 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000158024 SCV000606945 not provided Rasopathy no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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