Mutations in the cardiac Na⁺ channel gene SCN5A cause loss of function and underlie arrhythmia syndromes. SCN5A in humans has two splice variants, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077. We investigated the effect of splice variant background on loss of function and rescue for G1406R, a mutation reported to cause Brugada syndrome. Mutant and wild type (WT) channels in both backgrounds were transfected into HEK-293 cells and incubated for up to 72 hours with and without mexiletine. At 8 hours neither current nor cell surface expression were observed for the mutant in either background, but both were present in WT. At 24 hours small (<10% compared to WT) currents were noted and accompanied by cell surface expression. At 48 hours current density was ~40% of WT for the mutant in the Q1077del variant background, but remained at <10% of WT in Q1077. Current levels were stable by 72 hours. Co-expression with 1 or 3 subunits, or insertion of the polymorphism H558R in the background did not significantly affect current expression. Mexiletine restored current density of the mutant channel in both backgrounds to nearly WT levels. The mutant channels also showed a negative shift in inactivation, slower recovery, and enhanced slow inactivation consistent with a loss of function phenotype. These data show that a trafficking defect may be partial, time-dependent, and differ with the splice variant background. Also, both expression defects and gating abnormalities may contribute to loss of function for the same mutation.