ClinVar Miner

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

dbSNP: rs139734328
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Total submissions: 20
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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).

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