Submissions for variant NM_001005242.3(PKP2):c.1627G>A (p.Val543Ile)

gnomAD frequency: 0.00255  dbSNP: rs146102241

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148727	SCV000051589	benign	Arrhythmogenic right ventricular cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038184	SCV000061851	likely benign	not specified	2015-02-05	criteria provided, single submitter	clinical testing	p.Val587Ile in exon 8 of PKP2: This variant was initially believed to be likely disease causing based on its presence in 2 probands with ARVD/C and absence from 600 control chromosomes (Den Hann 2009, Basso 2006, Albuisson 2007). However, s everal studies identified this variant in 0.2%-0.8% of healthy control chromosom es (Christensen 2010: 3/1300; Fressart 2010: 3/600; Barahona-Dussault 2010: 0.08 %). Furthermore, it has been identified in 0.4% (252/66718) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs146102241). In summary, we cannot rule out that this variant modifies dis ease severity, but believe that it is unlikely disease causing when present in i solation.
CSER _CC_NCGL, University of Washington	RCV000148727	SCV000190461	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2014-06-01	criteria provided, single submitter	research	Allele frequency may indicate a low penetrance or likely benign variant
GeneDx	RCV001529002	SCV000236187	likely benign	not provided	2021-01-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31402444, 24055113, 24585727, 19955750, 22781308, 23299917, 20400443, 25637381, 21859740, 16774985, 19863551, 27153395, 26332594, 30656044)
Invitae	RCV000988812	SCV000288600	likely benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000250254	SCV000318069	benign	Cardiovascular phenotype	2017-03-10	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038184	SCV000698465	likely benign	not specified	2021-08-22	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1759G>A (p.Val587Ile) results in a conservative amino acid change located in the Armadillo (IPR000225) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 254134 control chromosomes, predominantly at a frequency of 0.0036 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.35 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Cardiomyopathy phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1759G>A has been reported in the literature in individuals affected with Cardiomyopathy (DenHaan_2009, Haas_2015, teRiele_2013, Baskin_2013, Basso_2006, Leong_2017, Connell_2018), but also in controls (Basso_2006, Christensen_2009, Fressart_2010, Kapplinger_2011). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in terms of stable expression and localization to the cell membrane (Kirchner_2012). Eleven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2), likely benign (n=5) and benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000038184	SCV000748001	uncertain significance	not specified	2017-06-29	criteria provided, single submitter	clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000038184	SCV000864333	likely benign	not specified	2017-11-21	criteria provided, single submitter	clinical testing	BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, 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	RCV000030360	SCV000902790	likely benign	Cardiomyopathy	2018-03-13	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852674	SCV000995381	likely benign	Ventricular tachycardia	2018-03-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000988812	SCV001138679	benign	Arrhythmogenic right ventricular dysplasia 9	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000988812	SCV001269283	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2017-04-27	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000030360	SCV001333849	benign	Cardiomyopathy	2017-10-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000988812	SCV001473204	benign	Arrhythmogenic right ventricular dysplasia 9	2021-01-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001529002	SCV003917199	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PKP2: BS2
PreventionGenetics, part of Exact Sciences	RCV003904872	SCV004720804	benign	PKP2-related disorder	2019-03-13	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV000148727	SCV004845982	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529002	SCV001741709	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038184	SCV001921206	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000038184	SCV001929368	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000038184	SCV001951244	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529002	SCV001966934	likely benign	not provided		no assertion criteria provided	clinical testing