Submissions for variant NM_001005242.3(PKP2):c.1539C>T (p.Asn513=)

gnomAD frequency: 0.00001  dbSNP: rs535581825

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156794	SCV000206515	likely benign	not specified	2014-09-24	criteria provided, single submitter	clinical testing	p.Asn557Asn in exon 7 of PKP2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 0.3% (57/16512) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs535581825).
Illumina Laboratory Services, Illumina	RCV000463611	SCV000378452	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000156794	SCV000534149	likely benign	not specified	2016-11-23	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	RCV000463611	SCV000557327	benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588739	SCV000698464	benign	not provided	2017-07-10	criteria provided, single submitter	clinical testing	Variant summary: The PKP2 c.1671C>T (p.Asn557Asn) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 60/121396 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.003452 (57/16512). This frequency is about 8 times the estimated maximal expected allele frequency of a pathogenic PKP2 variant (0.0004301), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000463611	SCV000743454	benign	Arrhythmogenic right ventricular dysplasia 9	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000463611	SCV000744699	likely benign	Arrhythmogenic right ventricular dysplasia 9	2017-06-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771815	SCV000904518	benign	Cardiomyopathy	2018-10-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399562	SCV002706144	benign	Cardiovascular phenotype	2020-08-13	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.
Fulgent Genetics, Fulgent Genetics	RCV000463611	SCV002810640	likely benign	Arrhythmogenic right ventricular dysplasia 9	2021-08-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588739	SCV004033196	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	PKP2: BP4, BP7
All of Us Research Program, National Institutes of Health	RCV003998323	SCV004845996	benign	Arrhythmogenic right ventricular cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000156794	SCV001918472	benign	not specified		no assertion criteria provided	clinical testing