ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.35A>G (p.Tyr12Cys)

gnomAD frequency: 0.00001  dbSNP: rs763433296
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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 RCV001178390 SCV001342828 uncertain significance Cardiomyopathy 2023-10-25 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 12 of the PKP2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/117646 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Invitae RCV001352524 SCV001547085 uncertain significance Arrhythmogenic right ventricular dysplasia 9 2023-11-02 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 12 of the PKP2 protein (p.Tyr12Cys). This variant is present in population databases (rs763433296, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 919919). 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. 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.
Ambry Genetics RCV003163401 SCV003859657 uncertain significance Cardiovascular phenotype 2023-02-16 criteria provided, single submitter clinical testing The p.Y12C variant (also known as c.35A>G), located in coding exon 1 of the PKP2 gene, results from an A to G substitution at nucleotide position 35. The tyrosine at codon 12 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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