Submissions for variant NM_001005242.3(PKP2):c.257dup (p.Tyr86Ter)

dbSNP: rs1555148271

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522421	SCV000621038	pathogenic	not provided	2017-10-05	criteria provided, single submitter	clinical testing	Although the c.257dupA (Y86X) variant in the PKP2 gene has not been reported as a pathogenic or benign to our knowledge, this variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay, in a gene for which loss-of-function is a known mechanism of disease. Though data from control individuals in publicly available databases is not available to assess the frequency of c.257dupA in the general population, a missense variant (c.258 T>G) in the PKP2 gene resulting in the same amino acid change (Y86X) is absent from large population cohorts (Lek et al., 2016), and is classified as pathogenic by GeneDx. Additionally, multiple other downstream nonsense variants in the PKP2 gene have been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014).
Ambry Genetics	RCV002431490	SCV002740357	pathogenic	Cardiovascular phenotype	2021-12-27	criteria provided, single submitter	clinical testing	The c.257dupA pathogenic mutation, located in coding exon 2 of the PKP2 gene, results from a duplication of A at nucleotide position 257, causing a translational frameshift with a predicted alternate stop codon (p.Y86*). This variant has been identified in several individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Groeneweg JA et al. Circ Cardiovasc Genet, 2015 Jun;8:437-46; Groeneweg JA et al. Am J Cardiol, 2013 Oct;112:1197-206; Cox MG et al. Circulation, 2011 Jun;123:2690-700; van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
All of Us Research Program, National Institutes of Health	RCV004003637	SCV004833990	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2023-07-19	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 2 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with PKP2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different DNA change (c.258T>G) resulting in the same amino acid change as this variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16567567). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.