Submissions for variant NM_001005242.3(PKP2):c.1418A>G (p.Asn473Ser)

gnomAD frequency: 0.00039  dbSNP: rs144536197

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172580	SCV000051037	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038168	SCV000061834	likely benign	not specified	2014-10-08	criteria provided, single submitter	clinical testing	p.Asn517Ser in exon7 of PKP2: This variant has been reported in 1 Caucasian indi vidual with sudden cardiac death (Ip 2013). While this variant is rare in the ge neral population (3/8600 European American chromosomes by the NHLBI Exome Sequen cing Project, http://evs.gs.washington.edu/EVS/; rs144536197), it appears to be common in Ashkenazi Jewish individuals (3/90 chromosomes, 3.3%; LMM unpublished data). In addition, asparagine (Asp) at position 517 is not conserved in mammals or evolutionarily distant species, supporting that a change at this position ma y be tolerated. In summary, the frequency of this variant in the Ashkenazi Jewis h population indicates it is likely benign, although a modifying effect cannot b e ruled out.
GeneDx	RCV000172580	SCV000236288	likely benign	not provided	2020-07-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362, 23962865, 27153395, 28301460)
Ambry Genetics	RCV000251493	SCV000318012	benign	Cardiovascular phenotype	2018-01-16	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086816	SCV000638866	likely benign	Arrhythmogenic right ventricular dysplasia 9	2025-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771855	SCV000904574	benign	Cardiomyopathy	2018-07-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038168	SCV000920005	likely benign	not specified	2022-01-03	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1550A>G (p.Asn517Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 282552 control chromosomes, predominantly at a frequency of 0.011 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Cardiomyopathy phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1550A>G has been reported in the literature in settings of multigene panel/WES testing as a likely benign variant in an individual affected with dilated right ventricle and in an individual with cancer (example, Ip_2013, Maxwell_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001086816	SCV001269796	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2019-08-02	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771855	SCV001332772	benign	Cardiomyopathy	2018-10-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172580	SCV004033197	likely benign	not provided	2025-01-01	criteria provided, single submitter	clinical testing	PKP2: BP4
Clinical Genetics, Academic Medical Center	RCV000172580	SCV001918063	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172580	SCV001931322	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172580	SCV001975127	likely benign	not provided		no assertion criteria provided	clinical testing