ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2365A>G (p.Ile789Val) (rs551045165)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 RCV000155881 SCV000236170 likely benign not specified 2017-11-24 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.
Illumina Clinical Services Laboratory,Illumina RCV000376789 SCV000378447 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000858400 SCV000761621 likely benign not provided 2018-07-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000613187 SCV000733156 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 9 no assertion criteria provided clinical testing

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