We estimate the penetrance of LQTS for KCNH2 S621R is 66%. This variant was found in a total of 2 carriers in 1 papers or gnomAD, 1 had LQTS. S621R is not present in gnomAD. S621R 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 S621R around 66% (7/12).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-4.876	0.999	-1	0.974	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
20167303	2010	2	1	1
LITERATURE, COHORT, AND GNOMAD:	-	2	1	1	-
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
621	0	S621R, S621R, S621R, S621N,
620	4	S620G, S620I,
622	5	L622F,
618	5	T618S, T618S,
644	5	V644F, V644I,
617	6	F617L, F617L, F617L, F617V,
645	6	M645L, M645V, M645I, M645I, M645R, M645I, M645L,
623	6	T623I,
624	6	S624N, S624R, S624R, S624R,
625	6	V625E,
641	7	S641P, S641F,
626	7	G626V, G626S, G626A,
625	7	V625E,
627	7	F627fsX, F627L, F627L, F627L, F627X,
619	7
648	8	G648A,
626	9	G626V, G626S, G626A,
640	9	F640L, F640Del, F640L, F640V, F640L,
623	9	T623I,
620	9	S620G, S620I,
564	9	L564L,
616	9	Y616S,
624	9	S624N, S624R, S624R, S624R,
627	9	F627fsX, F627L, F627L, F627L, F627X,
645	9	M645L, M645V, M645I, M645I, M645R, M645I, M645L,
642	10	I642Del, I642V,
647	10
561	10	A561T, A561P, A561V,
643	10
649	10
630	10	V630A, V630T, V630I,
568	10	W568C, W568C,
632	10	P632A, P632S,
615	10	L615F, L615V,
652	10	Y652X,
646	10
624	10	S624N, S624R, S624R, S624R,
631	11	S631F,
616	11	Y616S,
614	11	A614T, A614V,
565	11
628	11	G628A, G628Del, G628D, G628V, G628R, G628S,
619	11
557	11
626	11	G626V, G626S, G626A,
560	11	I560fsX, I560M,
642	12	I642Del, I642V,
651	12	M651K,
625	12	V625E,
638	12	K638E, K638D, K638R, K638Del,
625	12	V625E,
637	12	E637K, E637G, E637X,
641	12	S641P, S641F,
613	12	T613K, T613L, T613M, T613A,
621	13	S621R, S621R, S621R, S621N,
621	13	S621R, S621R, S621R, S621N,
628	13	G628A, G628Del, G628D, G628V, G628R, G628S,
626	13	G626V, G626S, G626A,
624	13	S624N, S624R, S624R, S624R,
649	13
629	13	N629K, N629D, N629T, N629S, N629K, N629I,
629	13	N629K, N629D, N629T, N629S, N629K, N629I,
639	13	I639F, I639N,
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, F617L, F617V,
638	14	K638E, K638D, K638R, K638Del,
627	14	F627fsX, F627L, F627L, F627L, F627X,
653	14
648	14	G648A,
562	14	H562Q, H562P, H562Q, H562R,
644	14	V644F, V644I,
618	14	T618S, T618S,
620	14	S620G, S620I,
632	14	P632A, P632S,
656	14	F656L, F656L, F656L,
612	14	V612A, V612L, V612L,
566	14	C566S, C566R, C566G, C566S, C566F,
623	15	T623I,
630	15	V630A, V630T, V630I,
615	15	L615F, L615V,
636	15
633	15	N633D, N633I, N633S,
563	15	W563G, W563C, W563X, W563C,
571	15	I571V, I571L,