SCN5A encodes the alpha subunit of the cardiac voltage-gated sodium channel. Wang et al. were the first to identify variants in this gene using linkage analysis in families with LQTS (PMID 7889574). An abundance of experimental data which has accumulated over the decades since this publication demonstrates gain-of-function as the pathophysiological mechanism leading to QT prolongation in affected patients. A large body of genetic evidence, including segregation and case-control data, further supports the association of SCN5A with LQTS leading to classification of this association as definitive.
Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams were reviewed by the LQTS Clinical Domain Expert Panel. For a detailed discussion of this group's work and the separate scores of the 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”
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