We estimate the penetrance of LQTS for KCNH2 V630I is 39%. This variant was found in a total of 7 carriers in 0 papers or gnomAD, 0 had LQTS. V630I is present in 7 alleles in gnomAD. V630I 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 V630I around 39% (6/17).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-0.967	0.937	3	0.735	83

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:	-	7	7	0	-
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
630	0	V630A, V630T, V630I,
631	4	S631F,
629	5	N629K, N629D, N629T, N629S, N629K, N629I,
628	5	G628A, G628Del, G628D, G628V, G628R, G628S,
617	6	F617L, F617L, F617L, F617V,
616	7	Y616S,
613	7	T613K, T613L, T613M, T613A,
585	7	W585C, W585C,
632	7	P632A, P632S,
588	8	N588K, N588K, N588D,
627	8	F627fsX, F627L, F627L, F627L, F627X,
627	8	F627fsX, F627L, F627L, F627L, F627X,
614	8	A614T, A614V,
589	8	L589P,
626	8	G626V, G626S, G626A,
568	8	W568C, W568C,
620	9	S620G, S620I,
592	9	Q592X,
629	9	N629K, N629D, N629T, N629S, N629K, N629I,
632	9	P632A, P632S,
638	9	K638E, K638D, K638R, K638Del,
628	9	G628A, G628Del, G628D, G628V, G628R, G628S,
633	9	N633D, N633I, N633S,
633	10	N633D, N633I, N633S,
631	10	S631F,
637	10	E637K, E637G, E637X,
621	10	S621R, S621R, S621R, S621N,
618	10	T618S, T618S,
584	10	G584C, G584R, G584S,
586	10	L586M,
641	11	S641P, S641F,
615	11	L615F, L615V,
612	11	V612A, V612L, V612L,
626	11	G626V, G626S, G626A,
628	11	G628A, G628Del, G628D, G628V, G628R, G628S,
625	11	V625E,
638	12	K638E, K638D, K638R, K638Del,
593	12	I593T, I593R, I593V, I593X, I593K,
590	12	G590D, G590V,
625	12	V625E,
565	12
626	12	G626V, G626S, G626A,
640	12	F640L, F640Del, F640L, F640V, F640L,
609	12	D609G, D609N,
641	12	S641P, S641F,
634	12	T634I, T634P, T634S, T634S, T634A,
616	12	Y616S,
591	12	D591H, D591N,
610	12
619	12
587	13
634	13	T634I, T634P, T634S, T634S, T634A,
642	13	I642Del, I642V,
630	13	V630A, V630T, V630I,
630	13	V630A, V630T, V630I,
572	13	G572D, G572C, G572S, G572R,
571	13	I571V, I571L,
592	13	Q592X,
569	13	Y569X, Y569C, Y569H,
645	13	M645L, M645V, M645I, M645I, M645R, M645I, M645L,
637	13	E637K, E637G, E637X,
635	13	N635I,
644	13	V644F, V644I,
583	14	I583V,
611	14	Y611D,
628	14	G628A, G628Del, G628D, G628V, G628R, G628S,
622	14	L622F,
564	14	L564L,
624	14	S624N, S624R, S624R, S624R,
645	14	M645L, M645V, M645I, M645I, M645R, M645I, M645L,
623	14	T623I,
636	14
620	14	S620G, S620I,
626	14	G626V, G626S, G626A,
629	14	N629K, N629D, N629T, N629S, N629K, N629I,
639	15	I639F, I639N,
621	15	S621R, S621R, S621R, S621N,
605	15	P605L,
561	15	A561T, A561P, A561V,
627	15	F627fsX, F627L, F627L, F627L, F627X,
567	15	I567T, I567M,
627	15	F627fsX, F627L, F627L, F627L, F627X,