AIMS: The variant in SCN5A with the loss of function (LOF) effect in the cardiac Na+ channel (Nav1.5) is the definitive cause for Brugada syndrome (BrS), and the functional analysis data revealed that LOF variants are associated with poor prognosis. However, which variant types (e.g. missense or non-missense) affect the prognoses of those variant carriers remain unelucidated. METHODS AND RESULTS: We defined SCN5A LOF variants as all non-missense and missense variants that produce peak INa <
65% of wild-type previously confirmed by patch-clamp studies. The study population consisted of 76 Japanese BrS patients (74% patients were male and the median age [IQR] at diagnosis was 28 [14-45] years) with LOF type of SCN5A variants: 40 with missense and 36 with non-missense variants. Non-missense variant carriers presented significantly more severe cardiac conduction disorder compared to the missense variant carriers. During follow-up periods of 9.0 [5.0-14.0] years, compared to missense variants, non-missense variants were significant risk factors of lifetime lethal arrhythmia events (LAEs) (P = 0.023). When focusing only on the missense variants that produce no peak INa, these missense variant carriers exhibited the same clinical outcomes as those with non-missense (log-rank P = 0.325). After diagnosis, however, both variant types were comparable in risk of LAEs (P = 0.155). CONCLUSION: We identified, for the first time, that SCN5A non-missense variants were associated with higher probability of LAE than missense variants in BrS patients though it did not change significantly after diagnosis.