Submissions for variant NM_001005242.3(PKP2):c.2233A>G (p.Ile745Val)

gnomAD frequency: 0.00004  dbSNP: rs551045165

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155881	SCV000205592	uncertain significance	not specified	2013-08-11	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Ile789Val varia nt in PKP2 has not been reported in individuals with cardiomyopathy or in large population studies. Isoleucine (Ile) at position 789 is not conserved in mammals or evolutionarily distant species and 1 species (bushbaby) carries a valine (Va l; this variant), raising the possibility that this change may be tolerated. Add itional computational analyses (biochemical amino acid properties, AlignGVGD, Po lyPhen2, and SIFT) also suggest that this variant may not impact the protein, th ough this information is not predictive enough to rule out pathogenicity. Althou gh this data supports that the Ile789Val variant may be benign, additional studi es are needed to fully assess its clinical significance.
GeneDx	RCV001706056	SCV000236170	likely benign	not provided	2021-06-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27066507, 25819062, 27535533)
Illumina Laboratory Services, Illumina	RCV000613187	SCV000378447	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000613187	SCV000761621	likely benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155881	SCV000920008	likely benign	not specified	2018-12-26	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.2365A>G (p.Ile789Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 276984 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 2.2 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. c.2365A>G has been reported in the literature in an individual affected with Cardiomyopathy, however this individual also carried another likely pathogenic MYH7 variant, c.1063G>A (p.Ala355Thr)that could explain his phenotype (Ceyhan-Birsoy 2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant twice as likely benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Klaassen Lab, Charite University Medicine Berlin	RCV000853144	SCV000995857	uncertain significance	Primary dilated cardiomyopathy	2019-07-03	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001187309	SCV001354076	likely benign	Cardiomyopathy	2018-10-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453521	SCV002735811	likely benign	Cardiovascular phenotype	2020-03-04	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000613187	SCV000733156	likely benign	Arrhythmogenic right ventricular dysplasia 9		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001706056	SCV001920701	likely benign	not provided		no assertion criteria provided	clinical testing