Submissions for variant NM_001005242.3(PKP2):c.2299C>A (p.Arg767Ser)

dbSNP: rs139734328

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000190558	SCV000051588	benign	Arrhythmogenic right ventricular cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038209	SCV000061877	likely benign	not specified	2017-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000858416	SCV000236190	benign	not provided	2018-05-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25637381, 20400443, 20857253, 23299917, 23810883, 24832006, 20829228, 23861362, 25351510, 26743238, 26656175, 26332594, 28341588, 29582136, 30731207, 31402444)
Ambry Genetics	RCV000244829	SCV000318609	likely benign	Cardiovascular phenotype	2018-10-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458904	SCV000557321	likely benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-28	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000458904	SCV000743445	likely benign	Arrhythmogenic right ventricular dysplasia 9	2017-06-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000458904	SCV000744692	likely benign	Arrhythmogenic right ventricular dysplasia 9	2017-05-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776101	SCV000910922	likely benign	Cardiomyopathy	2018-04-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000458904	SCV001138676	benign	Arrhythmogenic right ventricular dysplasia 9	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000858416	SCV001148690	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	PKP2: BS2
Illumina Laboratory Services, Illumina	RCV000458904	SCV001272955	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2019-08-02	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038209	SCV001362101	benign	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.2431C>A (p.Arg811Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0009 in 253076 control chromosomes (gnomAD, Fressart_2010, Klauke_2010, Tan_2010), including 1 homozygote in the gnomAD database. The observed variant frequency is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (0.00065), suggesting that the variant is benign. c.2431C>A has been reported in the literature in individuals affected with ARVD and other cardiological phenotypes (Fressart_2010, Klauke_2010, Tan_2010, Bottillo_2016, Proost_2017, Chua_2018, Sahlin_2019), however without strong evidence for pathogenicity (i.e. lack of co-segregation data), these reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. In addition, co-occurrences with other pathogenic variants have been reported in the literature (MYBPC3 c.3192dup (p.Lys1065fsX12), Bottillo_2016; DSG2 c.137G>A, p.Arg46Gln, Fressart_2010), providing supporting evidence for a benign role. 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: 24832006, 23299917, 26656175, 29582136, 20400443, 20829228, 23810883, 28341588, 30615648, 20857253). Eleven ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, seven as likely benign, and three as benign. Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000776101	SCV002043317	benign	Cardiomyopathy	2020-03-03	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV003318347	SCV004022020	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1, PP3
CSER _CC_NCGL, University of Washington	RCV000148730	SCV000190464	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2014-06-01	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000458904	SCV000733154	likely benign	Arrhythmogenic right ventricular dysplasia 9		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000858416	SCV001799796	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000858416	SCV001925606	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000858416	SCV001953349	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003934921	SCV004754302	likely benign	PKP2-related disorder	2019-05-30	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).