Background SCN5A is the most common susceptibility gene in patients with Brugada syndrome (BrS); however, the interpretation and management of benign or variants of unknown clinical significance (VUS) in SCN5A remains a challenge despite the availability of genetic testing. Objective This study aimed to investigate the relationship between the SCN5A variants and clinical symptoms of BrS patients. Methods We resequenced the SCN5A gene in 239 patients diagnosed with BrS at Hiroshima University Hospital and analyzed the association between the SCN5A variants and clinical features, 12-lead electrocardiography (ECG) parameters, or signal-averaged ECG. Results Overall, 84 SCN5A variants were identified: 55 benign, 7 pathogenic, and 22 VUS . No significant difference in the incidence of previous cardiac events was observed between patients with and without SCA5A benign variants. The female proportion was higher in BrS patients with SCN5A VUS or pathogenic variants. Moreover, the symptomatic proportion was higher in BrS patients with SCN5A VUS or pathogenic variants. Multivariate analyses revealed that the presence of SCN5A VUS or pathogenic variants, longer r-J interval in lead V1, and the presence of fragmented QRS were independently associated with the cardiac events in BrS patients and that positive late potentials, longer LAS40, and lower RMS40 were significantly associated with symptomatic BrS in patients carrying SCN5A VUS. Conclusions The SCN5A VUS or pathogenic variants were found to be independent risk factors for the cardiac events in the BrS patients. In BrS patients with SCN5A VUS, the signal-averaged ECG was the key to risk stratification for cardiac events.