Submissions for variant NM_001005242.3(PKP2):c.156G>A (p.Lys52=)

gnomAD frequency: 0.00092  dbSNP: rs201210997

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038169	SCV000061835	benign	not specified	2016-08-14	criteria provided, single submitter	clinical testing	p.Lys52Lys in exon 1 of PKP2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 1% (78/8192) of Lati no chromosomes, including 1 homozygote, by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs201210997).
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000229030	SCV000267450	likely benign	Arrhythmogenic right ventricular dysplasia 9	2016-03-18	criteria provided, single submitter	reference population
Invitae	RCV000229030	SCV000288594	benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000247345	SCV000319199	benign	Cardiovascular phenotype	2014-12-08	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health	RCV000771825	SCV000904532	benign	Cardiomyopathy	2018-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038169	SCV000920003	benign	not specified	2018-12-03	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.156G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0013 in 242920 control chromosomes, predominantly at a frequency of 0.0078 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 7.25 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 Latino origin. c.156G>A has been reported in the literature in individuals affected with Cardiomyopathy (Wu_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000229030	SCV001138684	benign	Arrhythmogenic right ventricular dysplasia 9	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000229030	SCV001266946	likely benign	Arrhythmogenic right ventricular dysplasia 9	2018-04-25	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV001705682	SCV001841808	benign	not provided	2020-03-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31402444, 26332594, 19302745)
Fulgent Genetics, Fulgent Genetics	RCV000229030	SCV002800218	benign	Arrhythmogenic right ventricular dysplasia 9	2021-09-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952435	SCV004772890	benign	PKP2-related condition	2019-08-07	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).