In Reply When health care clinicians are notified of an incidental “pathogenic” variant, they must determine the best course of action with respect to return of the result to the patient, further workup, and any therapeutic measures. In our study, to most closely simulate “real-world” results, variants identified in SCN5A and KCNH2 were classified as pathogenic or nonpathogenic by expert laboratories, the same laboratories that generate clinical reports and provide variant calls to databases like the Human Gene Mutation Database and ClinVar. As noted by Dr Biesecker, this approach resulted in a much higher frequency of pathogenic variants than the associated diseases, long QT syndrome and Brugada syndrome. Not surprisingly, owing to the low prevalence of these syndromes, review of the electronic health records of the research participants with these variants showed that they had not manifested disease.
Van Driest SL, Wells QS, Roden DM. Long QT Syndrome and Potentially Pathogenic Genetic Variants—In Reply. JAMA. 2016;315(22):2467-2468. doi:10.1001/jama.2016.2921