ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.634C>T (p.Arg212Cys) (rs766379716)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522400 SCV000619481 uncertain significance not provided 2017-07-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The R212C variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R212C 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.However, this substitution occurs at a position that is not conserved across species and where cysteine (C) is present as the wild type in at least two species. Finally, in silico analysis suggests that this variant likely does not alte the protein structure/function.
Ambry Genetics RCV000619187 SCV000736208 uncertain significance Cardiovascular phenotype 2019-02-05 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000794548 SCV000933963 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 212 of the PKP2 protein (p.Arg212Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs766379716, ExAC 0.001%). This variant has not been reported in the literature in individuals with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 450858). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Color RCV001187625 SCV001354476 uncertain significance Cardiomyopathy 2019-05-16 criteria provided, single submitter clinical testing

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