ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1372A>G (p.Ile458Val) (rs199571473)

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Total submissions: 8
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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, Partners HealthCare Personalized Medicine RCV000038160 SCV000061826 benign not specified 2015-12-23 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
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 General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Invitae RCV001085931 SCV000761635 benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000771888 SCV000904650 likely benign Cardiomyopathy 2018-03-13 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001085931 SCV001273073 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 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.
Integrated Genetics/Laboratory Corporation of America 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.

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