Submissions for variant NM_001005242.3(PKP2):c.1369_1372del (p.Lys456_Gln457insTer)

dbSNP: rs397516993

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038159	SCV000061825	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2011-04-27	criteria provided, single submitter	clinical testing	The Gln457X variant has been reported in one Caucasian proband with clinical fea tures of ARVC and was absent from 500 control chromosomes tested, cupporting a p athogenic role (Gerull 2004). In addition, this variant leads to a premature st op at codon 457, which is predicted to lead to a truncated or absent protein (lo ss of function). Loss of function of the PKP2 gene is an established disease mec hanism in patients with ARVD/C, which makes it highly likely that the Gln457X va riant is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003507249	SCV004295870	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln457*) 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, 23911551). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 31386562). ClinVar contains an entry for this variant (Variation ID: 45020). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003531935	SCV004358891	pathogenic	Cardiomyopathy	2023-05-02	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 5 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. This variant has been reported in at least five unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 25820315, 27572111, 30847666). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000038159	SCV004818851	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2023-03-23	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 5 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. This variant has been reported in at least five unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 25820315, 27572111, 30847666). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782030	SCV005394435	pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia	2024-09-30	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1369_1372delCAAA (p.Gln457X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250900 control chromosomes. c.1369_1372delCAAA has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g. Gerull_2004, van Lint_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15489853, 31386562). ClinVar contains an entry for this variant (Variation ID: 45020). Based on the evidence outlined above, the variant was classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530007	SCV001744485	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001530007	SCV001919842	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001530007	SCV001959939	pathogenic	not provided		no assertion criteria provided	clinical testing