The rapid delayed rectifier K+ current (IKr) is key to normal ventricular repolarization. Mutations to hERG (human Ether-à-go-go-Related gene) can result in either a loss or gain of function of channels responsible for IKr. The aim of this study was to investigate electrophysiological and pharmacological properties of a recently identified pore-mutation (T618I) associated with variant 1 short QT syndrome (SQTS) (Sun et al, 2011). Whole-cell patch clamp recordings of wild-type (WT) and T618I hERG current (IhERG) were made at 37oC from hERG-expressing HEK 293 cells, using previously described K+-based pipette solution and standard extracellular solution (El Harchi et al, 2012). Results are presented as mean ± S.E.M or mean ± 95% confidence interval (C.I). Statistical comparisons were made using unpaired t-tests. Under conventional voltage-clamp, voltage-dependent rectification was evident for both WT and T618I IhERG, though for T618I IhERG maximal current was ∼30 mV right-ward voltage-shifted compared to WT IhERG, consistent with a reported alteration to voltage-dependent inactivation for this mutation (Sun et al, 2011). The use of ventricular action potential (AP) voltage-clamp (“AP clamp”) revealed marked differences in the profile of WT and T618I IhERG during AP repolarisation. Maximal WT IhERG occurred comparatively late during the AP waveform, at -30.7 ± 1.2 mV (n=14), whilst for T618I hERG peak IhERG occurred significantly earlier during the ventricular AP plateau, at +5.1 ± 2.1 mV (n=19;P < 0.001 versus WT). The Class Ia antiarrhythmic drug disopyramide inhibited WT IhERG with a half-maximal inhibitory concentration (IC50) of 7.68 μM (C.I. 6.1 μM to 9.6 μM) and T618I IhERG with an IC50 of 16.8 μM (C.I 8.6 to 33.1 μM). The reported clinical concentration range of disopyramide lies between ∼6-8 μM (Zema, 1984) and therefore disopyramide may be predicted to retain some IhERG inhibitory activity in the setting of T618I-linked variant 1 SQTS. The occurrence of greater IhERG, earlier in the ventricular AP plateau is anticipated to lead to accelerated repolarization and hence AP and QT interval abbreviation.