Submissions for variant NM_001005242.3(PKP2):c.1881del (p.Lys628fs)

dbSNP: rs764817683

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183795	SCV000236276	pathogenic	not provided	2023-07-13	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies using patient derived cells demonstrated abnormal nuclear translocation of junction plakoglobin, suggesting mutant PKP2 transcripts are unstable and degraded to undetectable levels (Kim et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26389801, 25344329, 24585727, 23671136, 25815118, 27110425, 24657289, 24576884, 25971409, 24920660, 16549640, 24070718, 24967631, 21723241, 23889974, 19358943, 26590176, 20031617, 23810894, 17010805, 23871885, 20857253, 29221435, 30302938, 30205876, 31533459, 31386562, 31402444, 28097316, 33087929, 35653365, 35536239, 32485643, 23354045)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001842942	SCV000918022	pathogenic	Cardiac arrhythmia	2018-01-02	criteria provided, single submitter	clinical testing	Variant summary: The PKP2 c.2013delC (p.Lys672ArgfsX12) variant results in a premature termination codon, predicted to cause a truncated or absent PKP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2197_2202delinsG, p.His733fsX8; ). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/247018 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKP2 variant (0.0006502). The variant has been reported in numerous affected individuals and families, and has been reported to segregate in families with ARVD, albeit with less than full penetrance (Dalal_2006, Konig_2017, Arbustini_2014). A functional study has shown the variant leads to undetectable mutant cDNA levels indicating instability and degredation (Kim_2013). In addition, one clinical diagnostic laboratory/reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001183812	SCV001349645	pathogenic	Cardiomyopathy	2019-03-21	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 of the PKP2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23354045, 24967631, 25971409, 26590176). This variant has been identified in 2/251350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852371	SCV002119543	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys672Argfs*12) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 17041889, 23911551). This variant is present in population databases (rs764817683, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 16549640, 17010805, 24070718, 24585727, 29221435). It has also been observed to segregate with disease in related individuals. This variant is also known as 2011delC (p.671fsX683) and c.2009delC (p.K672RfsX12). ClinVar contains an entry for this variant (Variation ID: 202022). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002415788	SCV002720307	pathogenic	Cardiovascular phenotype	2020-08-31	criteria provided, single submitter	clinical testing	The c.2013delC pathogenic mutation, located in coding exon 10 of the PKP2 gene, results from a deletion of one nucleotide at nucleotide position 2013, causing a translational frameshift with a predicted alternate stop codon (p.K672Rfs*12). This alteration has been reported in individuals and families with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Dalal D et al. Circulation, 2006 Apr;113:1641-9; den Haan AD et al. Circ Cardiovasc Genet, 2009 Oct;2:428-35; Rigato I et al. Circ Cardiovasc Genet, 2013 Dec;6:533-42; König E et al. BMC Med. Genet., 2017 12;18:145). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017464	SCV004848345	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2023-05-22	criteria provided, single submitter	clinical testing	The p.Lys672ArgfsX12 variant in PKP2 has been reported in at least 6 individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) and segregated with disease in 7 affected relatives from 3 families (Tan 2010 PMID: 20857253, Philips 2014 PMID: 24585727, Kim 2013 PMID: 23354045, den Haan 2009 PMID: 20031617, Dalal 2006 PMID: 17010805 Dalal 2006 PMID: 16549640, Bauce 2011 PMID: 21723241, Arbustini 2014 PMID: 24768880, Alcalde 2014 PMID: 24967631, Mast 2017 PMID: 28097316, Konig 2017 PMID: 29221435, van Lint 2019 PMID: 31386562). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 202022) and has been identified in 0.0018% (1/68034) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 672 and leads to a premature termination codon 12 amino acids downstream. Heterozygous loss of function of the PKP2 gene is an established disease mechanism in autosomal dominant ARVC. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PVS1, PS4_moderate, PP1_Strong, PM2_Supporting.
All of Us Research Program, National Institutes of Health	RCV004017464	SCV005429446	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2024-08-13	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 of the PKP2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23354045, 24967631, 25971409, 26590176). This variant has been identified in 2/251350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.