Clinical impact of rare variants associated with inherited channelopathies: a 5-year update
Georgia Sarquella‐Brugada, Anna Fernández-Falgueras, Sergi César, Elena Arbelo, Mónica Coll, Alexandra Pérez‐Serra, Marta Puigmulé, Anna Iglesias, Mireia Alcalde, Marta Vallverdú-Prats, Victoria Fiol, Carles Ferrer‐Costa, Bernat del Olmo, Ferran Picó, Laura López, Ana García‐Álvarez, Paloma Jordà, Coloma Tirón de Llano, Rocío Toro, Simone Grassi, Antonio Oliva, Josép Brugada, Ramón Brugada, Óscar Campuzano
Abstract
A proper interpretation of the pathogenicity of rare variants is crucial before clinical translation. Ongoing addition of new data may modify previous variant classifications; however, how often a reanalysis is necessary remains undefined. We aimed to extensively reanalyze rare variants associated with inherited channelopathies originally classified 5 years ago and its clinical impact. In 2016, rare variants identified through genetic analysis were classified following the American College of Medical Genetics and Genomics' recommendations. Five years later, we have reclassified the same variants following the same recommendations but including new available data. Potential clinical implications were discussed. Our cohort included 49 cases of inherited channelopathies diagnosed in 2016. Update show that 18.36% of the variants changed classification mainly due to improved global frequency data. Reclassifications mostly occurred in minority genes associated with channelopathies. Similar percentage of variants remain as deleterious nowadays, located in main known genes (SCN5A, KCNH2 and KCNQ1). In 2016, 69.38% of variants were classified as unknown significance, but now, 53.06% of variants are classified as such, remaining the most common group. No management was modified after translation of genetic data into clinics. After 5 years, nearly 20% of rare variants associated with inherited channelopathies were reclassified. This supports performing periodic reanalyses of no more than 5 years since last classification. Use of newly available data is necessary, especially concerning global frequencies and family segregation. Personalized clinical translation of rare variants can be crucial to management if a significant change in classification is identified.