The human ether-a-go-go gene (hERG) encodes a voltage-dependent K⁺ ion channel (KCNH2) largely responsible for the rapid component of the delayed rectifier currents in the heart.  Loss of function mutations in hERG cause type-2 long QT syndrome (LQTS-2) and predispose affected individuals to cardiac arrhythmias.  Several classes of hERG channel variants have been described, including variants that affect channel gating, conductance and/or expression.  T1019PfsX38- and Q1070X-hERG are LQTS-2 causing variants reported in Oman and Saudi Arabia (Bhuiyan et al. 2008; Al Senaidi et al. 2014).  When expressed as cDNA in heterologous expression systems, these variants exhibited functional ion channels on the cell surface (Bhuiyan et al. 2008; Al Salmani et al. 2022)..  However, T1019PfsX38-hERG displayed characteristics of defective channel gating (Al Salmani et al. 2022).  In this study we try to test the responsiveness of T1019PfsX38- and Q1070X-hERG channels to the hERG channel activator N,N'-Bis[2-hydroxy-5-(trifluoromethyl)phenyl]urea (NS1643).  We expressed wild-type and the mutant channel variants in HEK293 cells and studied their electrophysiology using the whole-cell patch clamp technique.  We used paired and non-paired Student’s t-test where appropriate to assess the statistical significance of difference, n is the number of cells.  A 400 ms ventricular action potential (VAP) clamp revealed that T1019PfsX38- (p = 0.04) but not Q1070X-hERG (p = 0.774) exhibits reduced potassium currents at the repolarisation phase of the action potential (AP) (75-95 % of the AP duration) when compared with WT-hERG (I_(integral):.WT = 2.63 ± 0.29 pA.s/pF (n = 6), T1019PfsX38 = 1.43 ± 0.42 pA.s/pF (n=4), Q1070X = 2.94 ± 1.23 pA.s/pF (n = 4)).  The application of NS1643 (10 µM) to the bath solution increased these I_(integral) values by 53%, 80.3% and 78% in cells expressing WT- (p = 0.031, n=6), T1019PfsX38- (p = 0.001, n = 4) and Q1070X-hERG (p = 0.036, n = 4), respectively.  To understand these effects further, we measured the voltage and time dependences of channel activation in response to NS1643.  NS1643 shifted the half-maximum voltage (V_mid) of activation to more negative values (p < 0.01) compared to control but did not increase the maximal current amplitudes (control V_mid: WT =2.90 ± 3.25 mV (n = 5), T1019PfsX38 = 6.96 ± 4.94 mV (n = 3), Q1070X = 10.40 ± 2.40 mV (n = 5); NS1643 V_mid: WT = -16.70 ± 3.60 mV (n = 5), T1019PfsX38 = -13.57 ± 4.37 mV (n = 3), Q1070X = -15.38 ± 3.69 mV (n = 5)).  In addition, NS1643 accelerated the activation process of the three variants at multiple test potentials (p < 0.05, n = 4 – 9).  Moreover, NS1643 stabilised the open configuration of the channel and slowed the deactivation process when measured at -40 mV.  When applied to untransfected HEK293 cells, NS1643 (10 µM) inhibited endogenous currents that display fast activation and fast inactivation kinetics at potentials ≥ 0 mV (p < 0.01, n = 5).  Overall, NS1643 enhances the activities of WT-, T1019PfsX38- and Q1070X-hERG channels but its therapeutic potential require testing for undesired side effects.