We estimate the penetrance of LQTS for KCNH2 F29V is 29%. This variant was found in a total of 1 carriers in 1 papers or gnomAD (version 4), 1 had LQTS. F29V is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 7%; 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. F29V 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 F29V around 29% (3/11).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-4.177	0.04	-2	0.881	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
Italy Cohort	2020	1	0	1
LITERATURE, COHORT, AND GNOMAD:	-	1	0	1	-
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
29	0	F29L, F29L, F29V, F29S, F29L,
30	5	I30Del, I30T,
45	5	N45K, N45D, N45K,
27	6	R27P, R27X,
43	6	Y43C, Y43D,
128	6	N128S,
22	6	F22S, F22Y,
28	6	K28E,
31	7	I31S,
127	7
126	7
19	7	I19F,
48	7
129	7	F129C,
44	7	C44W, C44F, C44X,
47	8	G47V, G47C,
18	9	I18M,
23	9
26	9	S26I,
46	10	D46Y, D46E, D46E,
25	10	Q25P,
111	10	D111V,
21	10
49	11	C49G, C49R,
32	11	A32T,
42	11	I42N,
113	11	V113Del,
41	11	V41A,
798	11	I798fsX,
15	11	L15V,
24	11
56	11	R56Q,
130	11	E130K,
51	12
112	12	V112M,
125	12
110	12	V110A,
59	12
124	12	M124T, M124R,
50	12	E50X,
16	12	D16A,
17	12
64	13	C64R, C64Y,
60	13	M60T,
52	13	C52W,
20	13	R20L, R20G,
109	13	L109P, L109X, L109Q,
800	13
114	13	P114S,
115	13	V115M,
108	13	C108Y,
66	14	C66Y, C66G, C66R,
797	14	A797T,
14	14
40	14
799	14	L799sp,
801	14	K801T,
55	14	S55L,
131	15	V131fsX, V131L, V131L,
786	15
33	15	N33T,
53	15	G53S, G53R,
98	15
69	15	L69Del, L69P,