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

gnomAD frequency: 0.00073  dbSNP: rs200122872

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471728	SCV000557314	likely benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-30	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 Diagnostics, LLC DBA Color Health	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
All of Us Research Program, National Institutes of Health	RCV003996365	SCV004822680	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038152	SCV001923575	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723617	SCV001954127	likely benign	not provided		no assertion criteria provided	clinical testing