ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.964G>A (p.Gly322Ser) (rs200069860)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497362 SCV000590164 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PKP2 gene. The G322S variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G322S 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. Additionally, this substitution occurs at a position where only amino acids with similar properties to glycine (G) are tolerated across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV001237125 SCV001409876 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 322 of the PKP2 protein (p.Gly322Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs200069860, ExAC 0.01%). This variant has not been reported in the literature in individuals with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 432440). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). 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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