Submissions for variant NM_001005242.3(PKP2):c.1445C>T (p.Thr482Met)

gnomAD frequency: 0.00396  dbSNP: rs146882581

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000038172	SCV000051418	benign	not specified	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038172	SCV000061838	likely benign	not specified	2015-06-25	criteria provided, single submitter	clinical testing	p.Thr526Met in exon 7 of PKP2: This variant is not expected to have clinical sig nificance because it has been identified in 0.6% (60/10364) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs146882581).
Invitae	RCV000205511	SCV000261983	benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-31	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239283	SCV000297166	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2015-10-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621305	SCV000734898	likely benign	Cardiovascular phenotype	2018-09-27	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000038172	SCV000740391	likely benign	not specified	2016-10-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000205511	SCV000743455	likely benign	Arrhythmogenic right ventricular dysplasia 9	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000205511	SCV000744700	likely benign	Arrhythmogenic right ventricular dysplasia 9	2015-09-21	criteria provided, single submitter	clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000038172	SCV000864297	likely benign	not specified	2017-08-14	criteria provided, single submitter	clinical testing	BS1, BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory).
Color Diagnostics, LLC DBA Color Health	RCV000771145	SCV000902955	likely benign	Cardiomyopathy	2018-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038172	SCV000920009	likely benign	not specified	2018-06-04	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1577C>T (p.Thr526Met) results in a non-conservative amino acid change located in the Armadillo-type fold (IPR016024) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 278492 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 5.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmia phenotype (0.00043), strongly suggesting that the variant is benign. c.1577C>T has been reported in the literature in individuals affected with Arrhythmia. These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variant(s) have been reported (PKP2, p.L452*; DSP c.969_974delAAAAGA, p.E324_K325del; DES c.359C>A, p.A120D), providing supporting evidence for a benign role. (Rasmussen 2014, Rasmussen 2013, Brodehl 2013). These authors proposed that the variant of interest might modify the phenotype of other pathogenic variants (Rasmussen 2013) although no conclusive evidence supporting this notion has been published. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign (1x), likely benign (4x) or VUS (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852676	SCV000995383	benign	Brugada syndrome; Premature ventricular contraction	2019-01-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000205511	SCV001138680	benign	Arrhythmogenic right ventricular dysplasia 9	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000205511	SCV001269794	likely benign	Arrhythmogenic right ventricular dysplasia 9	2018-01-26	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771145	SCV001333850	benign	Cardiomyopathy	2017-12-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000205511	SCV001473706	benign	Arrhythmogenic right ventricular dysplasia 9	2023-10-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001705683	SCV001869177	benign	not provided	2018-12-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26332594, 27153395, 26764160, 21636032, 25637381, 23299917)
CeGaT Center for Human Genetics Tuebingen	RCV001705683	SCV002545019	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	PKP2: PM5, BP4, BS2
Dept of Medical Biology, Uskudar University	RCV003318346	SCV004021987	likely benign	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1, BP4
All of Us Research Program, National Institutes of Health	RCV000239283	SCV004846016	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148726	SCV000190458	likely benign	Familial isolated arrhythmogenic right ventricular dysplasia	2014-06-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000038172	SCV001919682	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000038172	SCV001953405	benign	not specified		no assertion criteria provided	clinical testing