We estimate the penetrance of LQTS for KCNQ1 G168R is 70%. This variant was found in a total of 56 carriers in 22 papers or gnomAD, 44 had LQTS. G168R is present in 3 alleles in gnomAD. G168R 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 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G168R around 70% (46/66).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-5.38	1.0	-3	0.937	43

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	10	None	10	None
31484877	2019	2	1	1	None
30758498	2019	8	None	8	None
27921062	2016	1	None	1	Duodenal ampullary adenoma
27041150	2016	2	2	None	None
26496715	2016	2	None	2	None
24667783	2015	2	1	1	None
24363352	2014	1	None	None	None
23631430	2013	6	None	None	None
23153844	2012	87	None	1	None
22949429	2012	3	None	3	None
22949429	2012	1	None	1	None
21956039	2011	5	None	5	None
21131640	2011	1	1	None	AF
19841300	2009	3	None	3	None
19716085	2009	15	None	15	None
19716085	2009	4	None	4	None
19490272	2009	66	None	66	None
17470695	2007	44	None	44	None
17192539	2006	1	None	1	None
14678125	2003	37	None	37	None
12566525	2003	1	None	1	None
LITERATURE, COHORT, AND GNOMAD:	-	56	12	44
VARIANT FEATURES ALONE:	-	10	8	2	-

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)
15051636	Oocytes	5	None	None	None
22456477	HEK		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)
15051636	Oocytes	30	None	None	None
22456477	HEK	20	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
168	0	G168R, G168R, G168R, G168R,
169	4	T169M, T169R,
171	6
167	6
170	6
165	6	V165M,
172	6	V172M, V172E,
166	6	F166V,
206	6	V206L,
164	7
173	8
203	9	L203P,
202	9	D202N, D202H,
174	9	R174H, R174C, R174L,
163	9
175	10	L175I,
205	10	V205M,
207	10	V207M, V207L, V207L, V207L, V207L, V207del,
162	10	V162M,
210	11	M210I, M210I, M210I,
176	11
209	11	S209P,
199	11	S199A,
240	11	H240R, H240P,
161	12
237	12
114	12
204	12	I204M, I204F,
208	12	A208V,
160	13	E160del, E160K, E160V,
129	13	V129I,
201	13	I201del,
125	13
194	13	A194P, A194T,
177	14	S177F,
200	14
198	14	I198V, I198T,
193	14	F193L, F193L, F193L,
233	14	L233P,
213	14
243	14	R243H, R243C, R243P, R243S,
115	14	E115A, E115G,
126	14	H126D,
110	15	V110I,
211	15
132	15	I132L,
159	15	M159del,
190	15	R190W, R190Q, R190L,
133	15	V133I,