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Background  A common SCN5A polymorphism H558R (c.1673 A > G,  rs1805124 ) improves sodium channel activity in mutated channels and known to be a genetic modifier of Brugada syndrome patients (BrS). We investigated clinical manifestations and underlying mechanisms of H558R in BrS.    Methods and results  We genotyped H558R in 100 BrS (mean age 45 ± 14 years; 91 men) and 1875 controls (mean age 54 ± 18 years; 1546 men). We compared clinical parameters in BrS with and without H558R (H558R+ vs. H558R- group,  N  = 9 vs. 91). We also obtained right atrial sections from 30 patients during aortic aneurysm operations and compared  SCN5A  expression and methylation with or without H558R. H558R was less frequent in BrS than controls (9.0% vs. 19.2%,  P  = 0.028). The VF occurrence ratio was significantly lower (0% vs. 29.7%,  P  = 0.03) and spontaneous type 1 ECG was less observed in H558R+ than H558R- group (33.3% vs. 74.7%,  P  = 0.01). The  SCN5A  expression level was significantly higher and the methylation rate was significantly lower in sections with H558R ( N  = 10) than those without (0.98 ± 0.14 vs. 0.83 ± 0.19,  P  = 0.04; 0.7 ± 0.2% vs. 1.6 ± 0.1%,  P  = 0.004, respectively). In BrS with heterozygous H558R, the A allele mRNA expression was 1.38 fold higher than G allele expression.    Conclusion  The SCN5A polymorphism H558R may be a modifier that protects against VF occurrence in BrS. The H558R decreased the SCN5A promoter methylation and increased the expression level in cardiac tissue. An allelic expression imbalance in BrS with a heterozygous H558R may also contribute to the protective effects in heterozygous mutations.    Electronic supplementary material  The online version of this article (doi: 10.1186/s12929-017-0397-x) contains supplementary material, which is available to authorized users.

H558R, a common SCN5A polymorphism, modifies the clinical phenotype of Brugada syndrome by modulating DNA methylation of SCN5A promoters