ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1171-10T>C (rs200122872)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038152 SCV000061818 likely benign not specified 2015-10-20 criteria provided, single submitter clinical testing c.1171-10T>C in intron 4 of PKP2: This variant is not expected to have clinical significance because a T>C change at this position does not diverge from the sp lice consensus and is therefore unlikely to impact splicing. It has been identif ied in 41/65854 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200122872).
GeneDx RCV000038152 SCV000171013 benign not specified 2014-02-28 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.
Illumina Clinical Services Laboratory,Illumina RCV000471728 SCV000378461 uncertain significance Arrhythmogenic right ventricular dysplasia 9 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000471728 SCV000557314 likely benign Arrhythmogenic right ventricular dysplasia 9 2020-12-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000038152 SCV000698460 likely benign not specified 2021-01-07 criteria provided, single submitter clinical testing Variant summary: PKP2 c.1171-10T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00043 in 250104 control chromosomes, predominantly at a frequency of 0.00092 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.4- fold the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00065), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1171-10T>C in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance (n=1) and likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000471728 SCV000743456 likely benign Arrhythmogenic right ventricular dysplasia 9 2014-10-09 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000471728 SCV000744703 likely benign Arrhythmogenic right ventricular dysplasia 9 2017-05-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000776186 SCV000911313 likely benign Cardiomyopathy 2018-09-29 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000776186 SCV001332777 likely benign Cardiomyopathy 2018-06-11 criteria provided, single submitter clinical testing
Clinical Genetics,Academic Medical Center RCV000038152 SCV001923575 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001723617 SCV001954127 likely benign not provided no assertion criteria provided clinical testing

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