We estimate the penetrance of LQTS for KCNH2 I82T is 37%. This variant was found in a total of 2 carriers in 1 papers or gnomAD (version 4), 2 had LQTS. I82T is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 0%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. I82T 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I82T around 37% (4/12).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-2.247	0.03	-1	0.787	70

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
23899126	2013	2	0	2	seizures
LITERATURE, COHORT, AND GNOMAD:	-	2	0	2	-
VARIANT FEATURES ALONE:	-	10	8	2	-

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
82	0	I82dup, I82T, I82Del, I82Ins,
83	4	A83P, A83fsX,
79	5	A79T, A79fsX, A79S, A79Del,
81	5	Q81E, Q81P, Q81X, Q81H, Q81H,
80	6	A80P,
85	6	A85P, A85V,
94	6	V94L, V94A, V94L,
65	7	T65P,
78	7	A78P, A78T,
84	7
86	7	L86R,
110	7	V110A,
112	8	V112M,
92	8	R92L, R92C,
64	8	C64R, C64Y,
96	9	I96T, I96V,
66	9	C66Y, C66G, C66R,
77	9	R77S,
127	9
87	10	L87P,
70	10	H70R, H70Q, H70Q,
76	10
111	11	D111V,
125	11
98	11
95	11	E95K, E95G,
90	11	E90K,
93	11	K93X, K93R,
88	11
67	11
109	11	L109P, L109X, L109Q,
75	11	Q75X,
63	12	P63H,
129	12	F129C,
69	12	L69Del, L69P,
74	12	T74M, T74fsX,
108	12	C108Y,
89	12	A89V, A89G,
39	12	C39R, C39X,
113	12	V113Del,
97	12
91	12
114	12	P114S,
30	13	I30Del, I30T,
126	13
128	13	N128S,
32	13	A32T,
68	14	F68L, F68L, F68L, F68V,
71	14	G71R, G71E, G71R, G71W,
38	14
41	15	V41A,
40	15
107	15	L107P,