We estimate the penetrance of LQTS for KCNH2 C108Y is 65%. This variant was found in a total of 4 carriers in 1 papers or gnomAD, 3 had LQTS. C108Y is not present in gnomAD. C108Y 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 C108Y around 65% (9/14).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-7.884	0.973	-3	0.881	62

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
28749435	2017	4	1	3
LITERATURE, COHORT, AND GNOMAD:	-	4	1	3	-
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
108	0	C108Y,
109	5	L109X, L109Q, L109P,
107	5	L107P,
131	5	V131L, V131L, V131fsX,
106	6	F106L, F106L, F106V, F106L,
96	6	I96T, I96V,
129	6	F129C,
98	6
110	6	V110A,
130	6	E130K,
95	6	E95G, E95K,
97	7
94	8	V94L, V94L, V94A,
51	9
28	9	K28E,
128	9	N128S,
105	10
111	10	D111V,
93	10	K93X, K93R,
69	10	L69Del, L69P,
100	11	R100Q, R100G, R100P,
127	11
99	11	Y99N, Y99S,
48	11
52	12	C52W,
74	12	T74fsX, T74M,
70	12	H70Q, H70R, H70Q,
78	12	A78P, A78T,
82	12	I82Del, I82Ins, I82dup, I82T,
112	12	V112M,
73	12	R73fsX, R73G, R73C, R73H,
66	12	C66R, C66G, C66Y,
75	13	Q75X,
104	13
79	13	A79T, A79Del, A79fsX, A79S,
47	13	G47C, G47V,
27	13	R27P, R27X,
30	13	I30Del, I30T,
29	13	F29S, F29V, F29L, F29L, F29L,
71	13	G71R, G71W, G71R, G71E,
81	13	Q81H, Q81P, Q81X, Q81E, Q81H,
65	14	T65P,
50	14	E50X,
68	14	F68L, F68L, F68V, F68L,
49	15	C49G, C49R,
126	15
92	15	R92C, R92L,
103	15
64	15	C64Y, C64R,
53	15	G53S, G53R,