Submissions for variant NM_001005242.3(PKP2):c.964G>T (p.Gly322Cys)

dbSNP: rs200069860

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766568	SCV000236212	likely benign	not provided	2019-08-30	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000208208	SCV000264141	uncertain significance	Ventricular fibrillation	2015-08-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000251473	SCV000318516	likely benign	Cardiovascular phenotype	2021-06-04	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.
Invitae	RCV001087213	SCV000545242	likely benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-25	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000183732	SCV000747979	uncertain significance	not specified	2017-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000183732	SCV000918019	likely benign	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.964G>T (p.Gly322Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 1614134 control chromosomes, predominantly at a frequency of 0.0011 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 at 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 African or African-American origin. c.964G>T has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual with unexplained cardiac arrest and in another individual with hypertrophic cardiomyopathy (HCM) (example, Mellor_2017, Lopes_2015).. 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. The following publications have been ascertained in the context of this evaluation (PMID: 25351510, 28600387). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=5) and VUS (n=2). 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	RCV000852677	SCV000995385	likely benign	Familial amyloid neuropathy	2019-05-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001181080	SCV001346156	likely benign	Cardiomyopathy	2020-03-05	criteria provided, single submitter	clinical testing