We estimate the penetrance of LQTS for KCNQ1 R231C is 57%. This variant was found in a total of 51 carriers in 13 papers or gnomAD, 30 had LQTS. R231C is present in 1 alleles in gnomAD. R231C 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R231C around 57% (34/61).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-7.69	1.0	-6	0.967	58

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	16	None	16	None
30758498	2019	1	None	1	None
26715165	2016	1	None	1	None
23193492	2012	3	1	2	AF
22613981	2012	8	6	2	AF
20850564	2011	18	11	7	None
19843919	2009	1	None	1	None
19716085	2009	1	None	1	None
17192539	2006	1	None	1	None
16922724	2006	1	None	1	bradycardia
15176425	2004	3	None	1	None
14998624	2004	3	3	None	None
12205790	2002	4	None	4	None
LITERATURE, COHORT, AND GNOMAD:	-	51	21	30
VARIANT FEATURES ALONE:	-	10	6	4	-

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)
19843919	CHO	5	None	None	None
30571187	HEK	52	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)
19843919	CHO	51	-4.0	None	1.0
30571187	HEK		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
231	0	R231C, R231H, R231S,
230	6
229	6	G229D,
140	6	S140G, S140R, S140R, S140R,
228	6
227	6
234	7	Q234H, Q234H,
144	7	T144A,
299	7
226	7	A226V,
278	8	Y278H,
143	8	S143F, S143P, S143Y,
232	8
281	8	Y281C,
141	8	V141M,
233	8	L233P,
235	9	I235N,
225	9	S225L, S225del,
282	9	L282P,
137	9	L137F, L137P,
285	10
136	10
156	11
298	11	S298I, S298N,
142	11
279	11	F279I,
222	11
277	11	S277L, S277del, S277P, S277W,
160	11	E160del, E160K, E160V,
145	11
275	11	F275del,
236	11	L236Q, L236R,
237	11
212	11
224	11	T224M,
139	11
274	12	I274V,
223	12
300	12	A300T, A300S,
153	12	T153M,
138	12
303	12	L303P,
297	12	G297S, G297D, G297R,
302	12	A302V, A302E, A302T,
152	12
280	12	V280A, V280E,
209	12	S209P,
149	12
283	13	A283G, A283T,
213	13
146	13	E146K, E146G, E146Q,
208	13	A208V,
276	13	S276del,
205	13	V205M,
238	14	M238V, M238L, M238L,
133	14	V133I,
286	14
221	14
301	14
296	14	F296S, F296L, F296L, F296L,
159	14	M159del,
157	14	F157C,
135	14
284	14	E284K,
148	14
155	14
154	14
217	15
134	15	L134P,
216	15	G216R,