We estimate the penetrance of LQTS for KCNQ1 S277L is 74%. This variant was found in a total of 37 carriers in 15 papers or gnomAD, 27 had LQTS. S277L is not present in gnomAD. S277L has been functionally characterized in 2 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S277L around 74% (34/47).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-5.83	1.0	-2	0.974	85

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
34135346	2021	1	1	None	None
32893267	2020	10	None	10	None
30758498	2019	10	None	3	None
29439887	2018	14	7	7	None
27041096	2016	1	None	1	None
26715165	2016	1	None	1	None
26496715	2016	1	None	1	None
24363352	2014	1	None	None	None
21895724	2011	3	2	1	None
21241800	2011	4	None	4	None
19716085	2009	2	None	2	None
19490272	2009	7	None	7	None
17470695	2007	3	None	3	None
14527360	2003	1	None	1	None
12808265	2003	1	None	1	None
LITERATURE, COHORT, AND GNOMAD:	-	37	10	27
VARIANT FEATURES ALONE:	-	10	3	7	-

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)
21241800	Oocytes	0	-8.7	None	None
21895724	CHO	0	0.0	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)
21241800	Oocytes	18	-8.7	None	None
21895724	CHO	10	0.0	1.0	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
277	0	S277L, S277del, S277P, S277W,
276	4	S276del,
302	5	A302V, A302E, A302T,
303	5	L303P,
280	5	V280A, V280E,
273	6	L273F, L273V, L273R,
274	6	I274V,
299	6
278	6	Y278H,
279	7	F279I,
275	7	F275del,
272	8	G272D, G272S, G272V,
281	8	Y281C,
300	9	A300T, A300S,
296	9	F296S, F296L, F296L, F296L,
282	9	L282P,
301	9
235	10	I235N,
283	10	A283G, A283T,
298	10	S298I, S298N,
284	10	E284K,
271	10
231	11	R231C, R231H, R231S,
270	11	F270S,
141	11	V141M,
232	11
318	11
269	11	G269D, G269S, G269del,
297	12	G297S, G297D, G297R,
137	12	L137F, L137P,
285	12
144	12	T144A,
140	13	S140G, S140R, S140R, S140R,
295	13
238	13	M238V, M238L, M238L,
330	13
234	13	Q234H, Q234H,
329	13	A329T,
236	14	L236Q, L236R,
228	14
229	14	G229D,
326	14
327	14	T327A, T327S, T327S,
333	14
307	15	V307L, V307L,
304	15	W304R, W304R,
138	15
315	15	Y315C, Y315S, Y315N, Y315H, Y315F,
268	15	I268V, I268S,
328	15	I328del,
313	15
308	15	V308F,
331	15
287	15	A287E, A287T, A287S,
145	15
325	15	G325R, G325R, G325E, G325W,