Submissions for variant NM_001005242.3(PKP2):c.1460T>G (p.Ile487Ser)

gnomAD frequency: 0.00417  dbSNP: rs147240502

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172579	SCV000054794	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038174	SCV000061840	benign	not specified	2015-04-08	criteria provided, single submitter	clinical testing	p.Ile531Ser in exon 7 of PKP2: This variant is not expected to have clinical sig nificance because it has been identified in 2.6% (170/6614) of Finnish chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs147240502).
GeneDx	RCV000038174	SCV000171016	benign	not specified	2013-01-25	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.
Blueprint Genetics	RCV000038174	SCV000207154	likely benign	not specified	2015-05-27	criteria provided, single submitter	clinical testing
Invitae	RCV000999858	SCV000288595	benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000249816	SCV000318195	benign	Cardiovascular phenotype	2015-08-14	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000999858	SCV000378453	likely benign	Arrhythmogenic right ventricular dysplasia 9	2018-02-01	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000439244	SCV000510680	likely benign	not provided	2016-09-16	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000439244	SCV000698463	benign	not provided	2016-09-12	criteria provided, single submitter	clinical testing	Variant summary: The PKP2 c.1592T>G (p.Ile531Ser) variant causes a missense change with 3/3 in silico tools (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively) predict a damaging outcome for this variant. This variant was found in 867/136406 control chromosomes (2 homozygotes) at a frequency of 0.006356, which is approximately 15 times the estimated maximal expected allele frequency of a pathogenic PKP2 variant (0.0004301), suggesting this variant is likely a benign polymorphism. In addition, multiple publications report the variant to co-occur with other potentially pathogenic variants. In the few small pedigrees published, the variant did not segregate within families, leading authors to conclude that this variant could be modulating the effect of another variant or this variant could have low penetrance. Furthermore, functional studies support the variant to have comparable to wild-type function. In addition, multiple reputable clinical diagnostic laboratories cite the variant as "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999858	SCV000885968	benign	Arrhythmogenic right ventricular dysplasia 9	2023-10-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770412	SCV000901855	likely benign	Cardiomyopathy	2016-01-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770412	SCV000910882	benign	Cardiomyopathy	2018-03-13	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852675	SCV000995382	benign	Family history of cardiomyopathy	2018-04-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000439244	SCV002545018	benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	PKP2: BP4, BS1, BS2