Table 1 Classification of KCNQ1 variants.
Classification*CriteriaVariants
INormal or higher surface trafficking levels, but low peak current density.
Dysfunctional channel.
V110l, C122Y, L134P, A150T, A150V, T169M, K218E, I227L, and
Q234P
IILow surface trafficking level but normal or higher channel function for the
minority of the population that reaches the plasma membrane.
Q107H and P197L
IIINormal or higher surface levels and peak current density but altered channel
V1/2 and/or deactivation rate.
H105L, R109L, T118S, and I132L
IVDefective in both channel properties and surface expression levels.T104I, L131P, E160K, K196T, P197S, L236P, and L236R
VSeverely expression- or trafficking-defective. Current is so low that channel
properties cannot be assessed.
Y111C, L114P, E115G, P117L, Y125D, H126L, ΔF167, R174C,
R174H, R174L, W176R, G179S, G189A, and R195P
VI (WT-like)Normal or higher properties in all testedV100I, A102S, T104S, H105N, H105Y, V106I, V124I, F127L,
A128T, V129I, V133I, V135A, V135I, A149V, and V207M

*The 32 mutants in classes I, II, IV, and V are all deemed to be LOF because they exhibit maximal channel conductance ≤65% of WT. Surface expression levels were deemed defective if they were ≤65% of WT. The four class III mutants exhibit normal maximal peak currents but altered V1/2 and/or deactivation rates and are therefore deemed dysfunctional.

The listed mutants are color-coded to indicate their initial classifications before this work: LQTS (red), VUS (blue), or neutral/benign (black).

H105L exhibited a hyperpolarizing shift in V1/2 for channel activation, R109L exhibited a hyperpolarizing shift in V1/2 for activation, T118S exhibited a depolarizing shift in V1/2 for activation, and I132L exhibited slowed deactivation.