Importance: Discordance in the interpretations of genetic test results has occurred with the increased number of laboratories that are performing testing. Differences in diagnostic interpretations may have implications for the treatment of patients. Objective: To assess the interlaboratory variation in the interpretations of genetic test results with potential therapeutic implications. Design, Setting, and Participants: In this cross-sectional study, 70 genes that are commonly tested in patients with epilepsy were examined to identify 22676 genetic variants from an unknown number of patients using the ClinVar public database of clinically annotated variants. Variant annotations submitted to ClinVar (data set version 2019-05) between November 16, 2012, and May 3, 2019, were included in the analysis. Conflicting interpretations of the genetic variants associated with epilepsy were analyzed for clinically substantial discrepancies between May 7 and June 29, 2019. Variants were examined only if they had been interpreted by 2 or more clinical laboratories. A variant with a clinically substantial difference in interpretation was defined as a variant that crossed the threshold between a likely pathogenic variant and a variant of uncertain significance. Main Outcomes and Measures: The frequency and types of variant interpretation conflicts were analyzed when a conflict was identified. Results: A total of 6292 of 22676 variants related to epilepsy (27.7%) were interpreted by 2 or more clinical laboratories. Many variants (3307 of 6292 [52.6%]) had interpretations that were fully concordant. However, 2985 variants (47.4%) had conflicting interpretations. A clinically substantial conflict was identified in 201 of 6292 variants (3.2%). Furthermore, 117 of 201 variants (58.2%) with differences in interpretation occurred in genes with therapeutic implications. Conclusions and Relevance: In this cross-sectional study, most interpretations of genetic variants associated with epilepsy were concordant among laboratories, but more than half of the variants with conflicting interpretations occurred in genes that have therapeutic implications. It would be helpful for genetic laboratories to report known diagnostic discordance with other clinical laboratories.

Original languageEnglish (US)
Article numbere203812
JournalJAMA Network Open
Issue number4
StatePublished - Apr 29 2020

ASJC Scopus subject areas

  • Medicine(all)


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