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Abstract —Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the α subunit of the cardiac Na + channel. In the present study, we report a novel LQTS-3 mutation, E1295K (EK), and describe its functional consequences when expressed in HEK293 cells. The clinical phenotype of the proband indicated QT interval prolongation in the absence of T-wave morphological abnormalities and a steep QT/R-R relationship, consistent with an LQTS-3 lesion. However, biophysical analysis of mutant channels indicates that the EK mutation changes channel activity in a manner that is distinct from previously investigated LQTS-3 mutations. The EK mutation causes significant positive shifts in the half-maximal voltage (V 1/2 ) of steady-state inactivation and activation (+5.2 and +3.4 mV, respectively). These gating changes shift the window of voltages over which Na + channels do not completely inactivate without altering the magnitude of these currents. The change in voltage dependence of window currents suggests that this alteration in the voltage dependence of Na + channel gating may cause marked changes in action potential duration because of the unique voltage-dependent rectifying properties of cardiac K + channels that underlie the plateau and terminal repolarization phases of the action potential. Na + channel window current is likely to have a greater effect on net membrane current at more positive potentials (EK channels) where total K + channel conductance is low than at more negative potentials (wild-type channels), where total K + channel conductance is high. These findings suggest a fundamentally distinct mechanism of arrhythmogenesis for congenital LQTS-3.