Submissions for variant NM_001005242.3(PKP2):c.1372A>G (p.Ile458Val)

gnomAD frequency: 0.00005  dbSNP: rs199571473

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172088	SCV000051034	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038160	SCV000061826	benign	not specified	2021-12-07	criteria provided, single submitter	clinical testing	The p.Ile458Val variant in PKP2 classified as benign because it not been previously reported in individuals with dilated cardiomyopathy but has been identified in 0.872% (267/30616) of South Asian chromosomes by gnomAD, including 5 homozygotes (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1.
GeneDx	RCV000038160	SCV000236222	benign	not specified	2017-01-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000617332	SCV000736894	benign	Cardiovascular phenotype	2017-08-08	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV001085931	SCV000761635	benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771888	SCV000904650	likely benign	Cardiomyopathy	2018-03-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001085931	SCV001273073	likely benign	Arrhythmogenic right ventricular dysplasia 9	2019-05-08	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038160	SCV001363124	likely benign	not specified	2019-11-25	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1372A>G (p.Ile458Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 250900 control chromosomes, predominantly at a frequency of 0.0087 within the South Asian subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 8-fold over 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 South Asian origin. c.1372A>G has been reported in the literature in individuals affected with Cardiomyopathy (Di Resta_2015, Lopes_2013, Pugh_2014). These reports 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. Five ClinVar submissions (evlauation after 2014) cite the variant four times a benign and once as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Genetics and Genomics Program, Sidra Medicine	RCV001293121	SCV001434111	likely benign	Primary dilated cardiomyopathy		criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000172088	SCV004010147	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PKP2: BS2
PreventionGenetics, part of Exact Sciences	RCV003914944	SCV004737350	likely benign	PKP2-related disorder	2019-05-27	no assertion criteria provided	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).