We estimate the penetrance of LQTS for KCNH2 C66Y is 33%. This variant was found in a total of 2 carriers in 1 papers or gnomAD (version 4), 2 had LQTS. C66Y 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. C66Y 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 C66Y around 33% (5/12).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-7.455	1.0	-3	0.895	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
France Cohort	2020	2	0	2
LITERATURE, COHORT, AND GNOMAD:	-	2	0	2	-
VARIANT FEATURES ALONE:	-	10	7	3	-

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
66	0	C66Y, C66G, C66R,
65	4	T65P,
67	5
68	5	F68L, F68L, F68L, F68V,
69	5	L69Del, L69P,
63	6	P63H,
64	6	C64R, C64Y,
70	6	H70R, H70Q, H70Q,
62	8	R62Q,
98	8
59	9
82	9	I82dup, I82T, I82Del, I82Ins,
41	9	V41A,
30	9	I30Del, I30T,
127	10
79	10	A79T, A79fsX, A79S, A79Del,
48	10
54	10	Y54N, Y54X,
39	10	C39R, C39X,
40	10
52	11	C52W,
96	11	I96T, I96V,
129	11	F129C,
83	11	A83P, A83fsX,
110	11	V110A,
71	11	G71R, G71E, G71R, G71W,
32	11	A32T,
38	12
58	12	E58K, E58D, E58D,
60	12	M60T,
74	12	T74M, T74fsX,
97	12
99	12	Y99S, Y99N,
86	12	L86R,
80	12	A80P,
108	12	C108Y,
125	13
78	13	A78P, A78T,
61	13	Q61R,
51	13
31	13	I31S,
44	13	C44W, C44F, C44X,
106	13	F106L, F106V, F106L, F106L,
112	13	V112M,
53	13	G53S, G53R,
94	13	V94L, V94A, V94L,
100	13	R100G, R100Q, R100P,
101	13	K101E,
49	13	C49G, C49R,
55	13	S55L,
85	14	A85P, A85V,
42	14	I42N,
29	14	F29L, F29L, F29V, F29S, F29L,
128	14	N128S,
57	14	A57P,
76	14
81	14	Q81E, Q81P, Q81X, Q81H, Q81H,
126	14
28	14	K28E,
75	14	Q75X,
109	15	L109P, L109X, L109Q,
72	15	P72S, P72R, P72T, P72Q,
111	15	D111V,
73	15	R73G, R73H, R73C, R73fsX,
43	15	Y43C, Y43D,
33	15	N33T,
45	15	N45K, N45D, N45K,
105	15
56	15	R56Q,