Submissions for variant NM_001005242.3(PKP2):c.972G>A (p.Ala324=)

gnomAD frequency: 0.00208  dbSNP: rs142636176

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038233	SCV000061901	benign	not specified	2013-01-13	criteria provided, single submitter	clinical testing	Ala324Ala in exon 3 of PKP2: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 0.6% (25/4406) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs142636176).
GeneDx	RCV000038233	SCV000236180	benign	not specified	2014-09-09	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	RCV000464866	SCV000557336	benign	Arrhythmogenic right ventricular dysplasia 9	2024-01-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770422	SCV000901865	benign	Cardiomyopathy	2017-04-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038233	SCV000918017	benign	not specified	2018-06-25	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.972G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within African control individuals in the gnomAD database is approximately 13.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmia phenotype (0.00043), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.972G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV000464866	SCV001269383	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.
Color Diagnostics, LLC DBA Color Health	RCV000770422	SCV001353183	benign	Cardiomyopathy	2018-11-08	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528981	SCV001741662	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038233	SCV001919008	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528981	SCV001980095	likely benign	not provided		no assertion criteria provided	clinical testing