The principal findings of this study are as follows: (1) that two KCNE1 variants associated with LQTS (A8V and D76N) and the D85N KCNE1 polymorphism decreased IhERG amplitude compared to that with WT KCNE1, with only modest accompanying changes in IhERG kinetics; (2) that the three KCNE1 variants studied here suppressed the IhERG response to premature stimuli compared to the response with WT KCNE1; and (3) the sensitivity of IhERG to pharmacological inhibition by cisapride and clarithromycin, but not quinidine, differed between variants and WT KCNE1 expression conditions. Here, KCNE1 is linked to familial long QT syndrome.