Submissions for variant NM_001005242.3(PKP2):c.505A>G (p.Ser169Gly)

gnomAD frequency: 0.00096  dbSNP: rs139139859

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172585	SCV000051416	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038222	SCV000061890	likely benign	not specified	2015-07-01	criteria provided, single submitter	clinical testing	p.Ser169Gly in exon 3 of PKP2: This variant has been reported in 1 athlete with features of ARVC and at least 1 individual with DCM (La Gerche 2010, Elliott 201 0), as well as in 3 individuals tested by our laboratory with cardiomyopathy and /or conduction system disease. However, this variant is not expected to have cli nical significance due to a lack of conservation across species, including mamma ls. Of note, 8 mammals have a glycine (Gly) at this position despite high nearby amino acid conservation. This variant has also been detected in 0.2% (39/16494) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; dbSNP rs139139859). Although a modifying role cannot be e xcluded, the presence of the variant amino acid in multiple mammals and its freq uency in the general population all support that it is likely benign.
CSER _CC_NCGL, University of Washington	RCV000148728	SCV000190462	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx	RCV000172585	SCV000236206	likely benign	not provided	2020-09-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31402444, 29802319, 25163546, 23861362, 25637381, 23299917, 24055113, 19863551, 20716751, 20525856, 26112193)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000148728	SCV000257986	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2015-02-13	criteria provided, single submitter	clinical testing
Invitae	RCV000464777	SCV000557319	likely benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617259	SCV000735915	likely benign	Cardiovascular phenotype	2018-10-22	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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000464777	SCV000744713	likely benign	Arrhythmogenic right ventricular dysplasia 9	2017-05-31	criteria provided, single submitter	clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000038222	SCV000864291	likely benign	not specified	2017-08-25	criteria provided, single submitter	clinical testing	BS1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769394	SCV000900786	benign	Cardiomyopathy	2022-09-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769394	SCV000910881	likely benign	Cardiomyopathy	2018-03-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038222	SCV000918023	likely benign	not specified	2020-11-02	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.505A>G (p.Ser169Gly) results in a non-conservative amino acid change in 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 0.0012 in 251282 control chromosomes, predominantly at a frequency of 0.0024 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6 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 a benign polymorphism found primarily in populations of South Asian origin. c.505A>G has been reported in the literature in individuals affected with Arrhythmia (LaGerche_2010, Nunn_2016), Suspected ARVC/D (Barahona-Dussault_2010), and Dilated Cardiomyopathy (Elliot_2010), but without strong evidence for pathogenicity. These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. The variant has also been found incidentally in several large cohorts in which exome sequencing was performed (Andreasen_2013, Dorschner_2013, Amendola_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 other ClinVar submitters (evaluation after 2014) cite the variant as likely benign/ benign (n=9) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000172585	SCV000987327	likely benign	not provided		criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852679	SCV000995387	likely benign	Hypertrophic cardiomyopathy	2018-11-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000464777	SCV001138683	benign	Arrhythmogenic right ventricular dysplasia 9	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000464777	SCV001271392	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000464777	SCV004562265	likely benign	Arrhythmogenic right ventricular dysplasia 9	2023-11-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003924926	SCV004743161	likely benign	PKP2-related disorder	2021-01-25	criteria provided, single submitter	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).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000038222	SCV000280416	uncertain significance	not specified	2014-10-16	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease
Clinical Genetics, Academic Medical Center	RCV000038222	SCV001924965	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172585	SCV001955288	likely benign	not provided		no assertion criteria provided	clinical testing