ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1114G>C (p.Ala372Pro) (rs200586695)

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Total submissions: 11
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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 RCV000172582 SCV000051038 likely benign Arrhythmogenic right ventricular cardiomyopathy 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038146 SCV000061812 uncertain significance not specified 2014-03-14 criteria provided, single submitter clinical testing The Ala372Pro in PKP2 has been reported in six probands with ARVC (den Haan 2009 , Xu 2010, Gehmlich 2011, Quarta 2011, LMM unpublished data), two of whom carrie d another variant likely to explain disease (Xu 2010 and Gehmlich 2011). This va riant has also been identified in 0.07% (6/8600) European American chromosomes b y the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu; dbSNP rs2005 86695). Computational prediction tools and conservation analyses suggest that th is variant may be benign though their accuracy is unknown. Additional studies ar e needed to fully assess its clinical significance.
GeneDx RCV000038146 SCV000236213 likely benign not specified 2017-06-16 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.
Invitae RCV001083681 SCV000557320 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000038146 SCV000604840 likely benign not specified 2017-03-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620638 SCV000735413 uncertain significance Cardiovascular phenotype 2017-06-16 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Subpopulation frequency in support of benign classification;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770419 SCV000901862 likely benign Cardiomyopathy 2017-09-14 criteria provided, single submitter clinical testing
Color RCV000770419 SCV000903369 likely benign Cardiomyopathy 2018-06-18 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000474453 SCV001148699 uncertain significance not provided 2019-10-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000038146 SCV001426911 likely benign not specified 2020-07-13 criteria provided, single submitter clinical testing Variant summary: PKP2 c.1114G>C (p.Ala372Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 394694 control chromosomes in the gnomAD database, including 1 homozygote (gnomAD v2 exomes dataset and v3 genomes dataset). The observed variant frequency is approximately 1.33 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 benign. Though the variant, c.1114G>C, has been reported in the literature in individuals affected with Arrhythmia (Xu_2010, Quarta_2011, Kant_2016, Maltese_2019), it was also reported in healthy controls (Xu_2010, Andreasen_2013). In addition, in most of the affected individuals/families carrying the variant, other (potentially) pathogenic variants were also present that could likely explain the disease phenotype (Xu_2010, Quarta_2011, Kant_2016); thus providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, i.e. five calling it likely benign, while two classifying it as a VUS. Based on the evidence outlined above, the variant was classified as likely benign.
Blueprint Genetics RCV000157412 SCV000207151 benign Primary familial hypertrophic cardiomyopathy 2013-11-08 no assertion criteria provided clinical testing

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