We estimate the penetrance of LQTS for KCNH2 C64F is 80%. We are unaware of any observations of this variant in individuals. C64F is not present in gnomAD. C64F 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 C64F around 80% (7/10).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-7.052	1.0	-3	0.896	82

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
LITERATURE, COHORT, AND GNOMAD:	-	0	0	0	-
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
64	0	C64R, C64Y,
65	4	T65P,
63	5	P63H,
39	5	C39R, C39X,
66	6	C66G, C66Y, C66R,
32	7	A32T,
40	7
41	7	V41A,
125	7
86	7	L86R,
127	8
30	8	I30Del, I30T,
82	8	I82dup, I82Del, I82Ins, I82T,
38	8
83	9	A83fsX, A83P,
62	9	R62Q,
67	9
31	9	I31S,
33	10	N33T,
34	10	A34T,
112	10	V112M,
59	10
85	10	A85P, A85V,
68	10	F68L, F68L, F68L, F68V,
42	10	I42N,
126	10
36	11	V36X,
69	11	L69Del, L69P,
124	11	M124T, M124R,
110	11	V110A,
60	11	M60T,
79	11	A79T, A79S, A79Del, A79fsX,
70	11	H70Q, H70Q, H70R,
87	12	L87P,
61	12	Q61R,
129	12	F129C,
48	12
37	12
114	12	P114S,
80	12	A80P,
98	13
113	13	V113Del,
29	13	F29V, F29L, F29S, F29L, F29L,
44	13	C44X, C44F, C44W,
35	13	R35W,
84	13
111	13	D111V,
43	13	Y43C, Y43D,
128	13	N128S,
796	13	V796L, V796L, V796Del,
122	13
94	13	V94L, V94A, V94L,
123	14
96	14	I96V, I96T,
81	14	Q81E, Q81P, Q81X, Q81H, Q81H,
92	14	R92C, R92L,
88	14
89	14	A89G, A89V,
78	14	A78P, A78T,
795	14	V795I,
90	14	E90K,
115	14	V115M,
52	15	C52W,
797	15	A797T,
54	15	Y54N, Y54X,
58	15	E58K, E58D, E58D,
798	15	I798fsX,
108	15	C108Y,