Submissions for variant NM_001005242.3(PKP2):c.1504G>A (p.Ala502Thr)

gnomAD frequency: 0.00016  dbSNP: rs368740836

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154801	SCV000204481	likely benign	not specified	2018-12-18	criteria provided, single submitter	clinical testing	The p.Ala546Thr variant in PKP2 is classified as likely benign because it has be en identified in 0.3% (91/35440) of Latino chromosomes, including two homozygote s, by gnomAD (http://gnomad.broadinstitute.org). Alanine (Ala) at position 546 i s not conserved in mammals or evolutionarily distant species and the chinchilla carries a threonine (Thr) at this position, raising the possibility that a chang e at this position may be tolerated. Additional computational tools suggest that this variant may not impact the protein. ACMG/AMP Criteria applied: BS1, BP4.
Ambry Genetics	RCV000245516	SCV000320189	likely benign	Cardiovascular phenotype	2017-03-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV001697114	SCV000536008	likely benign	not provided	2021-01-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21636032)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542133	SCV000638869	likely benign	Arrhythmogenic right ventricular dysplasia 9	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001178111	SCV001342467	likely benign	Cardiomyopathy	2018-10-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154801	SCV002570777	likely benign	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1636G>A (p.Ala546Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 251302 control chromosomes, predominantly at a frequency of 0.0026 within the Latino subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00065), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.1636G>A in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001178111	SCV004239573	benign	Cardiomyopathy	2022-08-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998271	SCV004846005	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2024-01-11	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001697114	SCV005216610	likely benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003952767	SCV004771521	likely benign	PKP2-related disorder	2019-07-10	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).