We estimate the penetrance of LQTS for KCNH2 S620R is 36%. We are unaware of any observations of this variant in individuals. S620R is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 4%; 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. S620R 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 S620R around 36% (3/10).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-4.769	0.999	-1	0.955	86

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
620	0	S620G, S620I,
621	4	S621R, S621N, S621R, S621R,
625	5	V625E,
626	5	G626A, G626V, G626S,
623	5	T623I,
617	5	F617L, F617L, F617L, F617V,
618	6	T618S, T618S,
619	6
616	6	Y616S,
627	6	F627fsX, F627L, F627X, F627L, F627L,
622	6	L622F,
645	6	M645I, M645L, M645R, M645L, M645V, M645I, M645I,
624	6	S624R, S624R, S624N, S624R,
625	7	V625E,
627	8	F627fsX, F627L, F627X, F627L, F627L,
642	8	I642V, I642Del,
641	9	S641F, S641P,
630	9	V630A, V630T, V630I,
615	9	L615F, L615V,
624	9	S624R, S624R, S624N, S624R,
626	9	G626A, G626V, G626S,
644	9	V644F, V644I,
626	9	G626A, G626V, G626S,
621	9	S621R, S621N, S621R, S621R,
628	9	G628V, G628R, G628D, G628Del, G628S, G628A,
614	10	A614T, A614V,
645	10	M645I, M645L, M645R, M645L, M645V, M645I, M645I,
641	10	S641F, S641P,
561	10	A561T, A561V, A561P,
629	10	N629S, N629T, N629K, N629I, N629D, N629K,
613	10	T613K, T613M, T613L, T613A,
624	10	S624R, S624R, S624N, S624R,
625	10	V625E,
631	11	S631F,
648	11	G648A,
638	11	K638E, K638R, K638D, K638Del,
632	11	P632S, P632A,
644	11	V644F, V644I,
646	11
564	11	L564L,
568	11	W568C, W568C,
652	11	Y652X,
557	11
649	11
565	11
623	11	T623I,
620	11	S620G, S620I,
620	11	S620G, S620I,
632	12	P632S, P632A,
640	12	F640L, F640L, F640L, F640Del, F640V,
626	12	G626A, G626V, G626S,
625	12	V625E,
648	12	G648A,
612	12	V612A, V612L, V612L,
631	12	S631F,
624	12	S624R, S624R, S624N, S624R,
622	12	L622F,
643	12
623	12	T623I,
628	13	G628V, G628R, G628D, G628Del, G628S, G628A,
560	13	I560M, I560fsX,
628	13	G628V, G628R, G628D, G628Del, G628S, G628A,
558	13	A558V, A558E, A558P,
649	13
617	13	F617L, F617L, F617L, F617V,
639	13	I639N, I639F,
647	13
616	13	Y616S,
627	13	F627fsX, F627L, F627X, F627L, F627L,
640	13	F640L, F640L, F640L, F640Del, F640V,
642	13	I642V, I642Del,
629	13	N629S, N629T, N629K, N629I, N629D, N629K,
643	13
585	14	W585C, W585C,
651	14	M651K,
647	14
611	14	Y611D,
630	14	V630A, V630T, V630I,
562	14	H562P, H562Q, H562Q, H562R,
637	14	E637G, E637K, E637X,
627	14	F627fsX, F627L, F627X, F627L, F627L,
633	14	N633D, N633I, N633S,
646	14
618	14	T618S, T618S,
621	14	S621R, S621N, S621R, S621R,
637	14	E637G, E637K, E637X,
652	15	Y652X,
656	15	F656L, F656L, F656L,
638	15	K638E, K638R, K638D, K638Del,
619	15
567	15	I567T, I567M,
566	15	C566G, C566R, C566S, C566S, C566F,