We estimate the penetrance of LQTS for KCNQ1 Y111C is 91%. This variant was found in a total of 96 carriers in 18 papers or gnomAD, 90 had LQTS. Y111C is present in 2 alleles in gnomAD. Y111C has been functionally characterized in 1 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Y111C around 91% (96/106).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-6.82	1.0	-4	0.95	81

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
33382510	2021	1	1	None	None
32893267	2020	9	None	9	None
32173736	2020	4	3	1	None
30758498	2019	1	None	1	None
29270100	2017	None	None	None	None
28720088	2017	148	None	74	None
27041096	2016	1	None	None	None
26019114	2015	70	None	None	None
25471708	2015	None	None	None	JLNS w/ vestibular DFx
24667783	2015	1	None	1	None
24052033	2013	60	None	None	None
22677073	2012	1	None	None	SUDS
22539601	2012	None	None	None	None
21129503	2011	170	None	26	None
20031635	2009	80	41	39	None
19716085	2009	5	None	5	None
19114714	2009	None	None	None	None
17053194	2006	None	None	None	None
LITERATURE, COHORT, AND GNOMAD:	-	96	6	90
VARIANT FEATURES ALONE:	-	10	4	6	-

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)
17053194	COS	0	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)
17053194	COS	10	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
111	0	Y111C,
112	5
115	5	E115A, E115G,
177	5	S177F,
180	6
108	6	G108S,
178	6	A178T, A178del,
116	6
114	6
110	6	V110I,
181	6	R181C,
174	7	R174H, R174C, R174L,
179	8	G179S,
107	8	Q107H, Q107H,
113	8
184	9	Y184S, Y184C, Y184D, Y184H,
193	9	F193L, F193L, F193L,
117	9	P117L,
244	9
173	9
175	10	L175I,
109	10	R109C, R109L,
243	10	R243H, R243C, R243P, R243S,
106	11
183	11	K183R,
176	11
190	11	R190W, R190Q, R190L,
182	11
122	11	C122Y,
170	12
118	12
196	12
105	12
171	12
126	12	H126D,
172	12	V172M, V172E,
199	13	S199A,
189	13	G189R, G189R, G189E,
119	13	G119R, G119V,
185	13	V185L, V185L, V185M, V185del,
198	13	I198V, I198T,
194	13	A194P, A194T,
104	14	T104A, T104I,
125	14
186	14	G186R, G186D,
245	14	G245V,
202	14	D202N, D202H,
121	15
242	15	D242N, D242Y,
192	15	R192C, R192H,