Submissions for variant NM_001005242.3(PKP2):c.1379-2067G>A

gnomAD frequency: 0.00070  dbSNP: rs138538072

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038163	SCV000061829	uncertain significance	not specified	2012-07-17	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Ala474Thr varia nt in PKP2 has been identified in 7/3738 African American chromosomes from a bro ad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs138538072). Computational analyses (biochemical amino acid prope rties, conservation, AlignGVGD, and PolyPhen2) suggest that the Ala474Thr varian t may not impact the protein, though this information is not predictive enough t o rule out pathogenicity. This data supports that the Ala474Thr variant may be b enign but is insufficient to rule out a role in disease. Additional studies are needed to fully assess its clinical significance.
Invitae	RCV000230907	SCV000288589	likely benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617449	SCV000734910	likely benign	Cardiovascular phenotype	2018-02-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770415	SCV000901858	benign	Cardiomyopathy	2021-11-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770415	SCV001353196	likely benign	Cardiomyopathy	2019-01-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038163	SCV001519421	likely benign	not specified	2022-07-19	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1420G>A (p.Ala474Thr) 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 0.00018 in 244150 control chromosomes, predominantly at a frequency of 0.0024 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American 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 African or African-American origin. c.1420G>A has been reported in the literature in individuals affected with dilated cardiomyopathy (Pugh_2014, Burstein_2020). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003924925	SCV004756659	likely benign	PKP2-related condition	2022-02-12	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).