ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.505A>G (p.Ser169Gly) (rs139139859)

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Total submissions: 16
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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 RCV000172585 SCV000051416 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038222 SCV000061890 likely benign not specified 2015-07-01 criteria provided, single submitter clinical testing p.Ser169Gly in exon 3 of PKP2: This variant has been reported in 1 athlete with features of ARVC and at least 1 individual with DCM (La Gerche 2010, Elliott 201 0), as well as in 3 individuals tested by our laboratory with cardiomyopathy and /or conduction system disease. However, this variant is not expected to have cli nical significance due to a lack of conservation across species, including mamma ls. Of note, 8 mammals have a glycine (Gly) at this position despite high nearby amino acid conservation. This variant has also been detected in 0.2% (39/16494) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; dbSNP rs139139859). Although a modifying role cannot be e xcluded, the presence of the variant amino acid in multiple mammals and its freq uency in the general population all support that it is likely benign.
CSER _CC_NCGL, University of Washington RCV000148728 SCV000190462 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000038222 SCV000236206 likely benign not specified 2017-11-16 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.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000148728 SCV000257986 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-02-13 criteria provided, single submitter clinical testing
Invitae RCV000172585 SCV000557319 likely benign not provided 2019-02-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617259 SCV000735915 likely benign Cardiovascular phenotype 2017-07-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000464777 SCV000744713 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-05-31 criteria provided, single submitter clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV000038222 SCV000864291 likely benign not specified 2017-08-25 criteria provided, single submitter clinical testing BS1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769394 SCV000900786 uncertain significance Cardiomyopathy 2015-09-11 criteria provided, single submitter clinical testing
Color RCV000769394 SCV000910881 likely benign Cardiomyopathy 2018-03-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000038222 SCV000918023 likely benign not specified 2019-08-19 criteria provided, single submitter clinical testing Variant summary: PKP2 c.505A>G (p.Ser169Gly) 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 0.0012 in 251282 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 5.58 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 South Asian origin. c.505A>G has been reported in the literature in individuals affected with Arrhythmia (LaGerche_2010, Nunn_2016), Suspected ARVC/D (Barahona-Dussault_2010), and Dilated Cardiomyopathy (Elliot_2010), but without strong evidence for pathogenicity. These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. The variant has also been found incidentally in several large cohorts in which exome sequencing was performed (Andreasen_2013, Dorschner_2013, Amendola_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) with conflicting assessments (uncertain significance X 2; likely benign X 7). Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000172585 SCV000987327 likely benign not provided criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852679 SCV000995387 likely benign Hypertrophic cardiomyopathy 2018-11-14 criteria provided, single submitter clinical testing
Mendelics RCV000464777 SCV001138683 benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-05-28 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000038222 SCV000280416 uncertain significance not specified 2014-10-16 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease

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