We estimate the penetrance of LQTS for KCNH2 I30T is 82%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. I30T is not present in gnomAD. I30T 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I30T around 82% (8/11).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-2.35	0.034	-1	0.825	88

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
19038855	2009	1	0	1	Seizure
LITERATURE, COHORT, AND GNOMAD:	-	1	0	1	-
VARIANT FEATURES ALONE:	-	10	3	7	-

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
30	0	I30Del, I30T,
127	5
31	5	I31S,
29	5	F29L, F29L, F29L, F29V, F29S,
43	6	Y43D, Y43C,
41	7	V41A,
126	7
44	7	C44X, C44W, C44F,
48	7
32	7	A32T,
129	7	F129C,
45	8	N45K, N45D, N45K,
64	8	C64Y, C64R,
128	8	N128S,
42	8	I42N,
59	9
125	9
28	9	K28E,
66	9	C66Y, C66G, C66R,
60	10	M60T,
40	10
112	10	V112M,
47	10	G47V, G47C,
27	10	R27X, R27P,
124	10	M124R, M124T,
798	10	I798fsX,
19	10	I19F,
110	11	V110A,
111	11	D111V,
22	11	F22Y, F22S,
49	11	C49G, C49R,
56	11	R56Q,
113	11	V113Del,
65	11	T65P,
63	11	P63H,
39	11	C39R, C39X,
33	11	N33T,
18	11	I18M,
52	12	C52W,
51	12
69	12	L69Del, L69P,
15	12	L15V,
62	12	R62Q,
46	12	D46E, D46E, D46Y,
797	12	A797T,
114	12	P114S,
68	12	F68V, F68L, F68L, F68L,
86	13	L86R,
796	13	V796L, V796Del, V796L,
98	13
82	13	I82Del, I82Ins, I82dup, I82T,
55	13	S55L,
61	13	Q61R,
115	13	V115M,
108	13	C108Y,
54	13	Y54N, Y54X,
130	13	E130K,
109	13	L109Q, L109X, L109P,
795	14	V795I,
34	14	A34T,
23	14
57	14	A57P,
50	14	E50X,
53	14	G53S, G53R,
58	14	E58D, E58D, E58K,
26	14	S26I,
799	14	L799sp,
123	14
25	14	Q25P,
67	14
85	14	A85V, A85P,
800	15
21	15
94	15	V94L, V94A, V94L,
36	15	V36X,
16	15	D16A,
14	15
38	15