Submissions for variant NM_001005242.3(PKP2):c.953A>C (p.His318Pro)

gnomAD frequency: 0.00004  dbSNP: rs181098323

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000617731	SCV000736221	likely benign	Cardiovascular phenotype	2019-06-18	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000415624	SCV001003031	likely benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000415624	SCV001269384	likely benign	Arrhythmogenic right ventricular dysplasia 9	2018-10-26	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV001175621	SCV001339290	likely benign	Cardiomyopathy	2020-02-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235203	SCV003933775	likely benign	not specified	2023-05-17	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.953A>C (p.His318Pro) 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 0.0037 in 328294 control chromosomes, including 10 homozygotes (gnomAD and jMorp databases (Tadaka_2021)). The observed variant frequency is approximately 5.72 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00065), strongly suggesting that the variant is benign. c.953A>C has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, however without strong evidence for causality (e.g., Ohno_2013, Wada_2017). These reports therefore do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. The following publications have been ascertained in the context of this evaluation (PMID: 33179747, 23514727, 29178656). Five ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments: 4 submitters classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV003995939	SCV004846456	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415624	SCV000493780	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2016-03-30	no assertion criteria provided	clinical testing