We estimate the penetrance of LQTS for KCNQ1 R190Q is 64%. This variant was found in a total of 26 carriers in 15 papers or gnomAD, 18 had LQTS. R190Q is present in 1 alleles in gnomAD. R190Q 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 R190Q around 64% (23/36).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-3.69	1.0	-1	0.951	57

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	9	None	3	None
27041150	2016	2	None	None	None
26496715	2016	1	None	1	None
24363352	2014	1	None	None	None
23631430	2013	4	None	None	None
22949429	2012	1	None	1	None
20660394	2010	4	3	1	None
19841300	2009	1	None	1	None
19716085	2009	3	None	3	None
19490272	2009	4	None	4	None
17470695	2007	4	None	4	None
17192539	2006	3	None	3	None
14678125	2003	4	None	4	None
10728423	2000	5	4	1	None
LITERATURE, COHORT, AND GNOMAD:	-	26	8	18
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
10728423	COS	0	None	None	None
10376919	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	30	None	None	None
10728423	COS	50	2.7	1.0	1.093846154
10376919	Oocytes	50	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
190	0	R190W, R190Q, R190L,
186	5	G186R, G186D,
189	5	G189R, G189R, G189E,
175	5	L175I,
178	5	A178T, A178del,
187	6	L187P, L187F,
193	6	F193L, F193L, F193L,
191	7
185	7	V185L, V185L, V185M, V185del,
184	7	Y184S, Y184C, Y184D, Y184H,
179	7	G179S,
188	8	W188C, W188C, W188G, W188S,
177	8	S177F,
176	8
194	8	A194P, A194T,
192	9	R192C, R192H,
172	10	V172M, V172E,
180	10
181	10	R181C,
183	10	K183R,
171	10
173	11
182	11
174	11	R174H, R174C, R174L,
195	11	R195Q, R195W,
111	11	Y111C,
107	11	Q107H, Q107H,
199	12	S199A,
196	12
115	13	E115A, E115G,
110	13	V110I,
108	13	G108S,
114	14
203	14	L203P,
200	14
170	15
168	15	G168R, G168R, G168R, G168R,
202	15	D202N, D202H,