ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1379-2019C>T (rs149930872)

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Total submissions: 17
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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 RCV000172581 SCV000051415 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000155807 SCV000205518 likely benign not specified 2013-11-04 criteria provided, single submitter clinical testing Arg490Trp in exon 6 of PKP2: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , orangutan, rhesus macaque, baboon, and marmoset have a tryptophan (Trp) at thi s position despite high nearby amino acid conservation. Addtionally, functional studies have shown that this variant does not impact splicing (Gandjbankhch 201 1). It has also been identified in 0.15% (7/4402) of African American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbS NP rs149930872). Arg490Trp in exon 6 of PKP2 (rs149930872; allele frequency = 0 .15%, 7/4402) **
PreventionGenetics,PreventionGenetics RCV000155807 SCV000310491 likely benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000155807 SCV000514128 likely benign not specified 2016-10-12 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 RCV000528781 SCV000638865 likely benign Arrhythmogenic right ventricular dysplasia 9 2020-11-04 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000577994 SCV000679904 uncertain significance Becker muscular dystrophy 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578052 SCV000679905 uncertain significance Dilated cardiomyopathy 3B 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000577936 SCV000679906 uncertain significance Duchenne muscular dystrophy 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000528781 SCV000679907 uncertain significance Arrhythmogenic right ventricular dysplasia 9 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578088 SCV000679908 uncertain significance Brugada syndrome 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000577930 SCV000679909 uncertain significance Primary dilated cardiomyopathy 2017-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619186 SCV000737479 likely benign Cardiovascular phenotype 2019-01-09 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Color Health, Inc RCV000771870 SCV000904593 likely benign Cardiomyopathy 2018-06-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000155807 SCV000920007 likely benign not specified 2021-03-01 criteria provided, single submitter clinical testing Variant summary: PKP2 c.1468C>T (p.Arg490Trp) 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. 4/4 computational tools (Alamut) predict no significant impact on normal splicing, which was confirmed by Gandjbakhch_2011 using transcriptional analysis in heart tissue. The variant allele was found at a frequency of 0.00042 in 231024 control chromosomes, predominantly at a frequency of 0.00093 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 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.1468C>T has been reported in the literature in individuals affected with arrhythmogenic right ventricular cardiomyopathy, sudden unexplained death and cardiac disease (Gandjbakhch_2011, Sanchez_2016). Additionally, one publication reported three siblings, including two reported as affected/possibly affected ARVC and one reported as unaffected, and suggested this variant is not fully penetrant or does not segregate with disease. Moreover, another variant (DSP p.Glu2343Lys) was found in all three family members and may explain the phenotype in these patients (Gandjbakhch_2011). Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely benign (n=5) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000771870 SCV000995384 likely benign Cardiomyopathy 2018-10-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000172581 SCV001148696 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000771870 SCV001332773 benign Cardiomyopathy 2018-02-16 criteria provided, single submitter clinical testing

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