ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1367A>G (p.Lys456Arg) (rs750897570)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183741 SCV000236221 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing p.Lys456Arg (AAA>AGA): c.1367 A>G in exon 5 of the PKP2 gene (NM_004572.3). The K456R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The K456R variant was not observed in approximately 6500 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 K456R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. No reported nearby missense mutations have been reported. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARVC panel(s).
Invitae RCV001049196 SCV001213235 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 456 of the PKP2 protein (p.Lys456Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs750897570, ExAC 0.002%). This variant has not been reported in the literature in individuals with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201982). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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