ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1759G>A (p.Val587Ile) (rs146102241)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250254 SCV000318069 benign Cardiovascular phenotype 2017-03-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148727 SCV000051589 benign Arrhythmogenic right ventricular cardiomyopathy 2013-06-24 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center 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
Color RCV000030360 SCV000902790 likely benign Cardiomyopathy 2018-03-13 criteria provided, single submitter clinical testing
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.
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).
Integrated Genetics/Laboratory Corporation of America RCV000030360 SCV000053027 likely benign Cardiomyopathy 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely benign.
Integrated Genetics/Laboratory Corporation of America RCV000590746 SCV000698465 likely benign not provided 2016-12-12 criteria provided, single submitter clinical testing Variant summary: The PKP2 c.1759G>A (p.Val587Ile) variant located in the Armadillo domain (via InterPro) causes a missense change involving a conserved nucleotide, while 3/5 in silico tools predict a benign outcome. A functional study found the protein to be stably expressed and localized to the cell membrane (Kirchner_2012). The variant of interest was found in controls (ExAC and publication controls) with an allele frequency of 294/124304 (1/422), which exceeds the estimated maximal expected allele frequency for a pathogenic PKP2 variant of 1/929, suggesting this variant is likely a benign polymorphism. The variant of interest has been reported in multiple affected individuals with cardiomyopathy, although cosegregation and co-occurrence data was not provided. Multiple clinical diagnostic laboratories and databases have cited the variant as "likely benign/benign." Therefore, until additional information becomes available, the variant of interest has been classified as "Likely Benign."
Invitae RCV000229931 SCV000288600 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-12-22 criteria provided, single submitter clinical testing
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,; 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.
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

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