We estimate the penetrance of LQTS for KCNH2 V113Del is 51%. This variant was found in a total of 3 carriers in 1 papers or gnomAD, 2 had LQTS. V113Del is not present in gnomAD. V113Del 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 V113Del around 51% (6/13).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
None	None	None	None	52

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
Italy Cohort	2020	3	1	2
LITERATURE, COHORT, AND GNOMAD:	-	3	1	2	-
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
113	0	V113Del,
114	4	P114S,
112	5	V112M,
126	5
111	6	D111V,
91	6
115	7	V115M,
90	7	E90K,
127	7
125	7
128	8	N128S,
89	9	A89V, A89G,
92	9	R92C, R92L,
93	10	K93X, K93R,
116	10	K116Q,
124	10	M124R, M124T,
110	10	V110A,
85	10	A85P, A85V,
86	10	L86R,
31	10	I31S,
122	10
22	11	F22Y, F22S,
18	11	I18M,
30	11	I30T, I30Del,
29	11	F29S, F29V, F29L, F29L, F29L,
32	11	A32T,
129	11	F129C,
123	11
88	12
94	12	V94A, V94L, V94L,
109	12	L109P, L109X, L109Q,
82	12	I82dup, I82Del, I82Ins, I82T,
64	13	C64R, C64Y,
21	13
121	13	A121fsX,
27	13	R27P, R27X,
15	13	L15V,
14	13
34	14	A34T,
25	14	Q25P,
87	14	L87P,
19	14	I19F,
33	14	N33T,
28	14	K28E,
117	14
83	14	A83P, A83fsX,
39	14	C39R, C39X,
130	14	E130K,
17	15
43	15	Y43C, Y43D,
81	15	Q81P, Q81H, Q81X, Q81H, Q81E,
120	15
65	15	T65P,