We estimate the penetrance of LQTS for KCNH2 V630A is 78%. This variant was found in a total of 2 carriers in 3 papers or gnomAD, 2 had LQTS. V630A is not present in gnomAD. V630A 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 V630A around 78% (9/12).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-3.867	0.985	0	0.966	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
11854117	2002	1	0	1
9693036	1998	1	0	1
15840476	2005	1	0	1
LITERATURE, COHORT, AND GNOMAD:	-	2	0	2	-
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
630	0	V630A, V630I, V630T,
631	4	S631F,
629	5	N629I, N629D, N629T, N629K, N629S, N629K,
628	5	G628S, G628A, G628V, G628D, G628R, G628Del,
617	6	F617V, F617L, F617L, F617L,
616	7	Y616S,
613	7	T613L, T613M, T613A, T613K,
585	7	W585C, W585C,
632	7	P632A, P632S,
588	8	N588K, N588K, N588D,
627	8	F627L, F627L, F627X, F627L, F627fsX,
627	8	F627L, F627L, F627X, F627L, F627fsX,
614	8	A614V, A614T,
589	8	L589P,
626	8	G626S, G626V, G626A,
568	8	W568C, W568C,
620	9	S620I, S620G,
592	9	Q592X,
629	9	N629I, N629D, N629T, N629K, N629S, N629K,
632	9	P632A, P632S,
638	9	K638D, K638R, K638E, K638Del,
628	9	G628S, G628A, G628V, G628D, G628R, G628Del,
633	9	N633I, N633D, N633S,
633	10	N633I, N633D, N633S,
631	10	S631F,
637	10	E637G, E637X, E637K,
621	10	S621R, S621R, S621R, S621N,
618	10	T618S, T618S,
584	10	G584C, G584R, G584S,
586	10	L586M,
641	11	S641F, S641P,
615	11	L615F, L615V,
612	11	V612L, V612A, V612L,
626	11	G626S, G626V, G626A,
628	11	G628S, G628A, G628V, G628D, G628R, G628Del,
625	11	V625E,
638	12	K638D, K638R, K638E, K638Del,
593	12	I593X, I593K, I593R, I593V, I593T,
590	12	G590V, G590D,
625	12	V625E,
565	12
626	12	G626S, G626V, G626A,
640	12	F640L, F640V, F640L, F640Del, F640L,
609	12	D609G, D609N,
641	12	S641F, S641P,
634	12	T634P, T634A, T634S, T634S, T634I,
616	12	Y616S,
591	12	D591N, D591H,
610	12
619	12
587	13
634	13	T634P, T634A, T634S, T634S, T634I,
642	13	I642V, I642Del,
630	13	V630A, V630I, V630T,
630	13	V630A, V630I, V630T,
572	13	G572D, G572S, G572R, G572C,
571	13	I571L, I571V,
592	13	Q592X,
569	13	Y569X, Y569C, Y569H,
645	13	M645R, M645L, M645V, M645L, M645I, M645I, M645I,
637	13	E637G, E637X, E637K,
635	13	N635I,
644	13	V644F, V644I,
583	14	I583V,
611	14	Y611D,
628	14	G628S, G628A, G628V, G628D, G628R, G628Del,
622	14	L622F,
564	14	L564L,
624	14	S624R, S624R, S624R, S624N,
645	14	M645R, M645L, M645V, M645L, M645I, M645I, M645I,
623	14	T623I,
636	14
620	14	S620I, S620G,
626	14	G626S, G626V, G626A,
629	14	N629I, N629D, N629T, N629K, N629S, N629K,
639	15	I639N, I639F,
621	15	S621R, S621R, S621R, S621N,
605	15	P605L,
561	15	A561P, A561V, A561T,
627	15	F627L, F627L, F627X, F627L, F627fsX,
567	15	I567M, I567T,
627	15	F627L, F627L, F627X, F627L, F627fsX,