We estimate the penetrance of LQTS for KCNH2 S621C is 29%. We are unaware of any observations of this variant in individuals. S621C is not present in gnomAD. We have tested the trafficking efficiency of this variant, 146% of WT with a standard error of 17%; 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. S621C 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 S621C around 29% (2/10).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-4.876	1.0	-1	0.945	75

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	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
621	0	S621R, S621N, S621R, S621R,
620	4	S620G, S620I,
622	5	L622F,
618	5	T618S, T618S,
644	5	V644I, V644F,
617	6	F617L, F617L, F617V, F617L,
645	6	M645I, M645I, M645R, M645I, M645L, M645V, M645L,
623	6	T623I,
624	6	S624R, S624R, S624R, S624N,
625	6	V625E,
641	7	S641P, S641F,
626	7	G626A, G626V, G626S,
625	7	V625E,
627	7	F627L, F627fsX, F627L, F627X, F627L,
619	7
648	8	G648A,
626	9	G626A, G626V, G626S,
640	9	F640L, F640V, F640L, F640Del, F640L,
623	9	T623I,
620	9	S620G, S620I,
564	9	L564L,
616	9	Y616S,
624	9	S624R, S624R, S624R, S624N,
627	9	F627L, F627fsX, F627L, F627X, F627L,
645	9	M645I, M645I, M645R, M645I, M645L, M645V, M645L,
642	10	I642Del, I642V,
647	10
561	10	A561P, A561V, A561T,
643	10
649	10
630	10	V630A, V630T, V630I,
568	10	W568C, W568C,
632	10	P632S, P632A,
615	10	L615F, L615V,
652	10	Y652X,
646	10
624	10	S624R, S624R, S624R, S624N,
631	11	S631F,
616	11	Y616S,
614	11	A614V, A614T,
565	11
628	11	G628Del, G628A, G628S, G628D, G628R, G628V,
619	11
557	11
626	11	G626A, G626V, G626S,
560	11	I560fsX, I560M,
642	12	I642Del, I642V,
651	12	M651K,
625	12	V625E,
638	12	K638R, K638D, K638Del, K638E,
625	12	V625E,
637	12	E637X, E637K, E637G,
641	12	S641P, S641F,
613	12	T613A, T613L, T613K, T613M,
621	13	S621R, S621N, S621R, S621R,
621	13	S621R, S621N, S621R, S621R,
628	13	G628Del, G628A, G628S, G628D, G628R, G628V,
626	13	G626A, G626V, G626S,
624	13	S624R, S624R, S624R, S624N,
649	13
629	13	N629T, N629S, N629D, N629I, N629K, N629K,
629	13	N629T, N629S, N629D, N629I, N629K, N629K,
639	13	I639N, I639F,
650	13	L650X,
622	13	L622F,
567	13	I567T, I567M,
646	13
558	13	A558P, A558E, A558V,
652	13	Y652X,
585	14	W585C, W585C,
617	14	F617L, F617L, F617V, F617L,
638	14	K638R, K638D, K638Del, K638E,
627	14	F627L, F627fsX, F627L, F627X, F627L,
653	14
648	14	G648A,
562	14	H562Q, H562Q, H562R, H562P,
644	14	V644I, V644F,
618	14	T618S, T618S,
620	14	S620G, S620I,
632	14	P632S, P632A,
656	14	F656L, F656L, F656L,
612	14	V612A, V612L, V612L,
566	14	C566G, C566S, C566F, C566R, C566S,
623	15	T623I,
630	15	V630A, V630T, V630I,
615	15	L615F, L615V,
636	15
633	15	N633D, N633I, N633S,
563	15	W563C, W563C, W563G, W563X,
571	15	I571L, I571V,