Background: Heterozygous carriers of the E161K mutation in the SCN5A gene, which encodes the Nav1.5 pore-forming subunit of the cardiac fast sodium channel (INa channel), show sinus node dysfunction. Voltage clamp experiments in expression systems have revealed data on mutation effects in absence and presence of the common H558R polymorphism in Nav1.5. Aim: We assessed the mechanism by which the E161K mutation causes sinus bradycardia and reduces atrial excitability as well as the potential role of the H558R polymorphism. Methods: We incorporated the mutation-induced changes in INa into the recently developed Fabbri-Severi model of a single human sinoatrial (SA) node cell. The threshold current of the Courtemanche-Ramirez-Nattel human right atrial cell model was used as a measure of atrial excitability. Results: The E161K mutation increased the cycle length of the SA nodal cell by 54 ms. Under vagal tone, through the simulated presence of 20 nM acetylcholine, this increase raised to 191 ms, reducing the beating rate from 49 to 42 beats/min. The mutant component of INa was effectively zero, thus slowing diastolic depolarization. Highly similar results were obtained with the H558R polymorphism. The E161K mutation increased the threshold stimulus current of the atrial cell by a factor of 2.3. The smaller shift in steady-state activation in case of the H558R polymorphism per se resulted in a smaller increase in threshold current, by a factor of 1.9, but in combination with the reduced availability of mutant INa channels through the polymorphism-induced −10-mV shift in steady-state inactivation, the threshold current was again increased by a factor of 2.3. Conclusion: We conclude that the experimentally identified mutation-induced changes in INa can explain the clinically observed sinus node dysfunction. Furthermore, we conclude that the common H558R polymorphism does not significantly alter the effects of the E161K mutation.