We estimate the penetrance of LQTS for KCNQ1 S225L is 64%. This variant was found in a total of 13 carriers in 15 papers or gnomAD, 9 had LQTS. S225L is present in 3 alleles in gnomAD. S225L has been functionally characterized in 3 papers. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S225L around 64% (14/23).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-5.7	0.994	0	0.873	63

PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

PubMed ID	Year	Carriers	Unaffected	LQT1	Other Disease
32893267	2020	15	None	15	None
30758498	2019	2	None	None	None
29688407	2018	1	1	None	None
26496715	2016	6	None	6	None
24606995	2014	1	None	1	None
23153844	2012	22	None	1	None
22949429	2012	2	None	2	None
22885918	2012	1	None	1	None
19841300	2009	2	None	2	None
19716085	2009	8	None	8	None
19590188	2009	None	None	None	None
19490272	2009	12	None	12	None
17470695	2007	13	None	13	None
17192539	2006	3	None	3	None
14678125	2003	2	None	2	None
LITERATURE, COHORT, AND GNOMAD:	-	13	4	9
VARIANT FEATURES ALONE:	-	10	5	5	-

Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

Peak current is relative to wildtype (100% being no different from wildtype). V_0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID	Cell Type	Peak Current IKs (%WT)	V1/2 Act.	Activation time (%WT)	Deactivation time (%WT)
22456477	HEK		None	None	None
11087258	Oocytes	10	11.0	None	None
19590188	Oocytes		None	None	None

Functional parameters are the same as defined above.

PubMed ID	Cell Type	Peak Current IKs (%WT)	V1/2 Act.	Activation time (%WT)	Deactivation time (%WT)
22456477	HEK	40	None	None	None
11087258	Oocytes	30	6.0	None	None
19590188	Oocytes	15	None	None	None

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: some residues appear multiple times at different distances. This results from the fact that the functional K_V7.1 channel is a homotetramer and occasionally the same residue from multiple subunits is present within the 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor	Distance (Angstroms)	Variants Observed in Individuals
225	0	S225L, S225del,
226	4	A226V,
224	4	T224M,
229	5	G229D,
221	5
228	5
227	5
212	6
223	6
222	6
230	7
211	8
208	9	A208V,
231	9	R231C, R231H, R231S,
215	9	V215M, V215G, V215L, V215L,
219	9	G219E,
220	9	Q220K,
233	9	L233P,
209	10	S209P,
213	10
232	10
216	10	G216R,
282	11	L282P,
217	11
214	11	C214Y,
234	12	Q234H, Q234H,
210	12	M210I, M210I, M210I,
278	12	Y278H,
207	13	V207M, V207L, V207L, V207L, V207L, V207del,
205	13	V205M,
160	13	E160del, E160K, E160V,
218	13
157	13	F157C,
285	13
236	14	L236Q, L236R,
140	14	S140G, S140R, S140R, S140R,
204	14	I204M, I204F,
235	14	I235N,
281	14	Y281C,
237	14
144	14	T144A,
206	14	V206L,
143	14	S143F, S143P, S143Y,
156	14
279	14	F279I,
153	14	T153M,
161	15