We estimate the penetrance of LQTS for KCNH2 V630D is 34%. We are unaware of any observations of this variant in individuals. V630D is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 0%; 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. V630D 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V630D around 34% (3/10).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-6.767	0.998	-3	0.974	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:	-	0	0	0	-
VARIANT FEATURES ALONE:	-	10	7	3	-

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