High-Throughput Reclassification of SCN5A Variants.

American Journal of Human Genetics
Andrew M GlazerDan M Roden

Abstract

Partial or complete loss-of-function variants in SCN5A are the most common genetic cause of the arrhythmia disorder Brugada syndrome (BrS1). However, the pathogenicity of SCN5A variants is often unknown or disputed; 80% of the 1,390 SCN5A missense variants observed in at least one individual to date are variants of uncertain significance (VUSs). The designation of VUS is a barrier to the use of sequence data in clinical care. We selected 83 variants: 10 previously studied control variants, 10 suspected benign variants, and 63 suspected Brugada syndrome-associated variants, selected on the basis of their frequency in the general population and in individuals with Brugada syndrome. We used high-throughput automated patch clamping to study the function of the 83 variants, with the goal of reclassifying variants with functional data. The ten previously studied controls had functional properties concordant with published manual patch clamp data. All 10 suspected benign variants had wild-type-like function. 22 suspected BrS variants had loss of channel function (<10% normalized peak current) and 22 variants had partial loss of function (10%-50% normalized peak current). The previously unstudied variants were initially classified as l...Continue Reading

Citations

Jul 11, 2020·Expert Opinion on Drug Discovery·Alison ObergrussbergerNiels Fertig
Sep 8, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Roddy WalshConnie R Bezzina
Jan 15, 2021·European Heart Journal·Pieter G PostemaConnie R Bezzina
Feb 4, 2021·Nature Reviews. Neuroscience·Miriam H MeislerWenxi Yu
Feb 1, 2021·International Journal of Cardiology·Roddy Walsh
Mar 25, 2021·American Journal of Human Genetics·Valentina FavalliLuca Mazzarella
Jun 12, 2021·Heart Rhythm O2·Daniela Ponce-Balbuena, Isabelle Deschênes
Apr 30, 2021·Circulation·Joyce C K ManVincent M Christoffels
Sep 22, 2021·Human Genetics·Georgia Sarquella-BrugadaOscar Campuzano
Sep 24, 2021·The Journal of Physiology·Alison ObergrussbergerNiels Fertig

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