ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1627G>A (p.Val543Ile) (rs146102241)

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Total submissions: 14
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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 RCV000148727 SCV000051589 benign Arrhythmogenic right ventricular cardiomyopathy 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038184 SCV000061851 likely benign not specified 2015-02-05 criteria provided, single submitter clinical testing p.Val587Ile in exon 8 of PKP2: This variant was initially believed to be likely disease causing based on its presence in 2 probands with ARVD/C and absence from 600 control chromosomes (Den Hann 2009, Basso 2006, Albuisson 2007). However, s everal studies identified this variant in 0.2%-0.8% of healthy control chromosom es (Christensen 2010: 3/1300; Fressart 2010: 3/600; Barahona-Dussault 2010: 0.08 %). Furthermore, it has been identified in 0.4% (252/66718) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs146102241). In summary, we cannot rule out that this variant modifies dis ease severity, but believe that it is unlikely disease causing when present in i solation.
CSER _CC_NCGL, University of Washington RCV000148727 SCV000190461 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-06-01 criteria provided, single submitter research Allele frequency may indicate a low penetrance or likely benign variant
GeneDx RCV000038184 SCV000236187 benign not specified 2013-11-07 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 RCV000988812 SCV000288600 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000250254 SCV000318069 benign Cardiovascular phenotype 2017-03-10 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Integrated Genetics/Laboratory Corporation of America RCV000038184 SCV000698465 likely benign not specified 2020-08-03 criteria provided, single submitter clinical testing Variant summary: PKP2 c.1759G>A (p.Val587Ile) results in a conservative amino acid change located in the Armadillo (IPR000225) of 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 0.0024 in 285534 control chromosomes, predominantly at a frequency of 0.0096 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9 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 found primarily in populations of Non-Finnish European origin. c.1759G>A has been reported in the literature in individuals affected with Cardiomyopathy (DenHaan_2009, Haas_2015, teRiele_2013, Baskin_2013, Basso_2006, Leong_2017, Connell_2018), but also in controls (Basso_2006, Christensen_2009, Fressart_2010, Kapplinger_2011). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Kirchner_2012). Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x), likely benign (5x) and benign (3x). Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000038184 SCV000748001 uncertain significance not specified 2017-06-29 criteria provided, single submitter clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV000038184 SCV000864333 likely benign not specified 2017-11-21 criteria provided, single submitter clinical testing BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory).
Color RCV000030360 SCV000902790 likely benign Cardiomyopathy 2018-03-13 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852674 SCV000995381 likely benign Ventricular tachycardia 2018-03-26 criteria provided, single submitter clinical testing
Mendelics RCV000988812 SCV001138679 benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000988812 SCV001269283 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-04-27 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000030360 SCV001333849 benign Cardiomyopathy 2017-10-31 criteria provided, single submitter clinical testing

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