ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1379-2067G>A (rs138538072)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038163 SCV000061829 uncertain significance not specified 2012-07-17 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ala474Thr varia nt in PKP2 has been identified in 7/3738 African American chromosomes from a bro ad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs138538072). Computational analyses (biochemical amino acid prope rties, conservation, AlignGVGD, and PolyPhen2) suggest that the Ala474Thr varian t may not impact the protein, though this information is not predictive enough t o rule out pathogenicity. This data supports that the Ala474Thr variant may be b enign but is insufficient to rule out a role in disease. Additional studies are needed to fully assess its clinical significance.
Invitae RCV000230907 SCV000288589 likely benign Arrhythmogenic right ventricular dysplasia 9 2020-11-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617449 SCV000734910 likely benign Cardiovascular phenotype 2018-02-05 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770415 SCV000901858 uncertain significance Cardiomyopathy 2016-02-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000770415 SCV001353196 likely benign Cardiomyopathy 2019-01-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000038163 SCV001519421 likely benign not specified 2021-03-15 criteria provided, single submitter clinical testing Variant summary: PKP2 c.1420G>A (p.Ala474Thr) 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 0.00026 in 275522 control chromosomes, predominantly at a frequency of 0.0027 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmia phenotype (0.00043), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1420G>A has been reported in the literature in one individual affected with early onset DCM (Pugh_2014). The report does not provide unequivocal conclusions about association of the variant with Arrhythmia. One co-occurrence with another pathogenic KCNQ1 variant has been reported internally, providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.

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