We estimate the penetrance of LQTS for KCNH2 P114S is 52%. This variant was found in a total of 19 carriers in 3 papers or gnomAD, 11 had LQTS. P114S is not present in gnomAD. P114S has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P114S around 52% (15/29).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-6.243	0.876	-2	0.963	45

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	LQT2	Other Disease
Japan Cohort	2020	8	2	6
France Cohort	2020	10	5	5
16922724	2006	1	1
LITERATURE, COHORT, AND GNOMAD:	-	19	8	11	-
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.

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 since the functional K_V11.1 channel (protein product of KCNH2/hERG) 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
114	0	P114S,
113	4	V113Del,
115	5	V115M,
125	6
90	6	E90K,
89	6	A89G, A89V,
112	6	V112M,
116	6	K116Q,
126	6
122	7
91	8
124	8	M124T, M124R,
86	8	L86R,
123	9
85	9	A85V, A85P,
88	9
111	9	D111V,
127	9
92	9	R92C, R92L,
121	9	A121fsX,
32	10	A32T,
34	11	A34T,
117	11
31	11	I31S,
87	11	L87P,
120	11
128	12	N128S,
33	12	N33T,
18	12	I18M,
93	12	K93R, K93X,
30	12	I30T, I30Del,
110	12	V110A,
64	12	C64Y, C64R,
82	12	I82T, I82dup, I82Ins, I82Del,
39	13	C39X, C39R,
14	13
83	13	A83fsX, A83P,
15	13	L15V,
29	13	F29L, F29S, F29L, F29L, F29V,
22	13	F22Y, F22S,
94	14	V94L, V94L, V94A,
84	14
118	14	E118X, E118K, E118D, E118D,
119	14	D119H, D119G,
35	14	R35W,
129	14	F129C,
42	15	I42N,
40	15
65	15	T65P,