ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1928A>G (p.Lys643Arg) (rs533659697)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000543714 SCV000638875 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 643 of the PKP2 protein (p.Lys643Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs533659697, ExAC 0.05%). This variant has not been reported in the literature in individuals with a PKP2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine 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, this variant has uncertain impact on PKP2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000620310 SCV000737545 uncertain significance Cardiovascular phenotype 2016-07-13 criteria provided, single submitter clinical testing Insufficient evidence
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757663 SCV000885971 uncertain significance not provided 2017-06-20 criteria provided, single submitter clinical testing The p.Lys643Arg variant (rs533659697) has not been reported in the medical literature and is not listed in gene-specific variant databases. It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in East Asian populations of 0.03% (identified in 6 out of 17,242 chromosomes). The lysine at codon 643 is moderately conserved considering 8 species (Alamut software v2.9), and computational analyses suggest this variant does not have a significant effect on PKP2 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Lys643Arg variant cannot be determined with certainty.
Color RCV001184764 SCV001350825 uncertain significance Cardiomyopathy 2019-09-30 criteria provided, single submitter clinical testing

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