ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1183C>T (p.Arg395Cys)

gnomAD frequency: 0.00002  dbSNP: rs761238380
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001177383 SCV001341581 uncertain significance Cardiomyopathy 2019-01-15 criteria provided, single submitter clinical testing This missense variant is located in the armadillo repeat 2 of the PKP2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/245810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002339442 SCV002638335 uncertain significance Cardiovascular phenotype 2019-10-22 criteria provided, single submitter clinical testing The p.R395C variant (also known as c.1183C>T), located in coding exon 5 of the PKP2 gene, results from a C to T substitution at nucleotide position 1183. The arginine at codon 395 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV003507358 SCV004270867 uncertain significance Arrhythmogenic right ventricular dysplasia 9 2023-06-20 criteria provided, single submitter clinical testing This variant is present in population databases (rs761238380, gnomAD 0.003%). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 919284). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 395 of the PKP2 protein (p.Arg395Cys).

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