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Background: PathogenicRYR2 variants account for ≈60% of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benignRYR2 variants identified in the general population remains a challenge for genetic test interpretation. Therefore, we examined the results of theRYR2 genetic test among patients referred for commercial genetic testing and examined factors impacting variant interpretability.Methods: Frequency and location comparisons were made forRYR2 variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls. The impact of the clinical phenotype on the yield ofRYR2 variants was examined. Six in silico tools were assessed using patient- and control-derived variants.Results: A total of 18.2% (218/1200) of patients referred for commercial testing hosted rareRYR2 variants, statistically less than the 59% (46/78) yield among clinically definite cases, resulting in a much higher potential genetic false discovery rate among referrals considering the 3.2% background rate of rare, benignRYR2 variants. Exclusion of clearly putative pathogenic variants further complicates the interpretation of the next novelRYR2 variant. Exonic/topologic analyses revealed overrepresentation of patient variants in exons covering only one third of the protein. In silico tools largely failed to show evidence toward enhancement of variant interpretation.Conclusions: Current expert recommendations have resulted in increased use ofRYR2 genetic testing in patients with questionable clinical phenotypes. Using the largest to date catecholaminergic polymorphic ventricular tachycardia patient versus control comparison, this study highlights important variables in the interpretation of variants to overcome the 3.2% background rate that confoundsRYR2 variant interpretation.

Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation