SCN5A and Brugada syndrome 1: Another example of the modulatory effect of a missense polymorphism on disease allele penetrance is provided by the His558Arg substitution (rs1805124) in the SCN5A gene in a case of Brugada syndrome type 1 caused by compound heterozygous mutations (Asp1690Asn and Gly1748Asp) in SCN5A. Both mutations reduced the peak Na+ current density due to limited trafficking of the SCN5A protein towards the membrane, but Gly1748Asp also profoundly affected channel gating.