ClinVar Miner

Submissions for variant NM_030662.3(MAP2K2):c.692G>A (p.Arg231His) (rs730880511)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000788005 SCV000927037 uncertain significance Noonan syndrome and Noonan-related syndrome 2019-05-17 reviewed by expert panel curation The c.692G>A (p.Arg231His) variant in MAP2K2 has been identified in a patient with clinical features consistent with cardiomyopathy (PS4 not met; Invitae internal data, GTR Lab ID 500031; ClinVar SCV000776886.1). 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.Arg231His variant may impact the protein (PP3). In summary, the clinical significance of the p.Arg231His variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3.
Invitae RCV000654976 SCV000776886 uncertain significance Rasopathy 2017-11-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 231 of the MAP2K2 protein (p.Arg231His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with MAP2K2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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