We estimate the penetrance of LQTS for KCNH2 S624C is 69%. We are unaware of any observations of this variant in individuals. S624C is not present in gnomAD. S624C 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 S624C around 69% (6/10).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-4.876	1.0	-1	0.942	74

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	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
624	0	S624R, S624R, S624N, S624R,
625	4	V625E,
623	4	T623I,
625	5	V625E,
624	5	S624R, S624R, S624N, S624R,
624	5	S624R, S624R, S624N, S624R,
621	6	S621R, S621R, S621N, S621R,
620	6	S620G, S620I,
626	7	G626V, G626S, G626A,
623	7	T623I,
624	7	S624R, S624R, S624N, S624R,
622	7	L622F,
652	7	Y652X,
625	8	V625E,
626	8	G626V, G626S, G626A,
625	8	V625E,
645	8	M645I, M645V, M645L, M645I, M645R, M645I, M645L,
626	9	G626V, G626S, G626A,
645	9	M645I, M645V, M645L, M645I, M645R, M645I, M645L,
648	9	G648A,
620	9	S620G, S620I,
623	9	T623I,
627	9	F627L, F627fsX, F627L, F627X, F627L,
649	9
621	9	S621R, S621R, S621N, S621R,
627	9	F627L, F627fsX, F627L, F627X, F627L,
626	9	G626V, G626S, G626A,
649	10
652	10	Y652X,
619	10
652	10	Y652X,
644	10	V644I, V644F,
620	10	S620G, S620I,
623	10	T623I,
621	10	S621R, S621R, S621N, S621R,
648	11	G648A,
618	11	T618S, T618S,
622	11	L622F,
622	11	L622F,
617	11	F617L, F617L, F617V, F617L,
641	12	S641F, S641P,
653	12
652	12	Y652X,
627	12	F627L, F627fsX, F627L, F627X, F627L,
656	12	F656L, F656L, F656L,
619	12
627	12	F627L, F627fsX, F627L, F627X, F627L,
616	12	Y616S,
620	12	S620G, S620I,
557	12
651	12	M651K,
647	12
644	12	V644I, V644F,
646	12
641	12	S641F, S641P,
646	12
621	13	S621R, S621R, S621N, S621R,
628	13	G628Del, G628A, G628S, G628V, G628R, G628D,
642	13	I642Del, I642V,
648	13	G648A,
653	13
650	13	L650X,
645	13	M645I, M645V, M645L, M645I, M645R, M645I, M645L,
642	13	I642Del, I642V,
656	13	F656L, F656L, F656L,
645	13	M645I, M645V, M645L, M645I, M645R, M645I, M645L,
649	13
616	13	Y616S,
628	14	G628Del, G628A, G628S, G628V, G628R, G628D,
649	14
622	14	L622F,
630	14	V630T, V630I, V630A,
561	14	A561P, A561T, A561V,
647	14
650	14	L650X,
643	14
618	14	T618S, T618S,
628	14	G628Del, G628A, G628S, G628V, G628R, G628D,
617	14	F617L, F617L, F617V, F617L,
617	14	F617L, F617L, F617V, F617L,
653	14
655	14
615	14	L615F, L615V,
648	14	G648A,
631	14	S631F,
618	15	T618S, T618S,
619	15
557	15
640	15	F640Del, F640L, F640V, F640L, F640L,
564	15	L564L,
560	15	I560fsX, I560M,
632	15	P632A, P632S,
629	15	N629S, N629T, N629D, N629K, N629I, N629K,
628	15	G628Del, G628A, G628S, G628V, G628R, G628D,
651	15	M651K,
654	15