We estimate the penetrance of LQTS for KCNH2 V94L is 71%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. V94L is not present in gnomAD. V94L 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V94L around 71% (7/11).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-1.467	0.284	1	0.495	77

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	1	0	1
LITERATURE, COHORT, AND GNOMAD:	-	1	0	1	-
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.

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
94	0	V94L, V94A, V94L,
110	4	V110A,
95	5	E95G, E95K,
81	6	Q81H, Q81P, Q81X, Q81E, Q81H,
93	6	K93R, K93X,
109	6	L109X, L109Q, L109P,
82	6	I82Del, I82T, I82Ins, I82dup,
96	7	I96T, I96V,
78	7	A78T, A78P,
92	7	R92L, R92C,
112	8	V112M,
111	8	D111V,
108	8	C108Y,
79	8	A79T, A79S, A79Del, A79fsX,
85	9	A85P, A85V,
80	9	A80P,
91	10
77	10	R77S,
129	10	F129C,
97	10
98	10
83	10	A83P, A83fsX,
127	11
107	11	L107P,
84	11
75	11	Q75X,
128	11	N128S,
90	11	E90K,
86	12	L86R,
113	12	V113Del,
130	12	E130K,
65	12	T65P,
74	12	T74fsX, T74M,
76	12
131	13	V131L, V131fsX, V131L,
70	13	H70Q, H70R, H70Q,
66	13	C66Y, C66G, C66R,
64	13	C64R, C64Y,
106	14	F106V, F106L, F106L, F106L,
126	14
114	14	P114S,
69	14	L69Del, L69P,
88	14
89	14	A89V, A89G,
125	14
73	14	R73fsX, R73C, R73G, R73H,
30	15	I30T, I30Del,
28	15	K28E,
87	15	L87P,