We estimate the penetrance of LQTS for KCNH2 G628Del is 44%. This variant was found in a total of 1 carriers in 1 papers or gnomAD (version 4), 1 had LQTS. G628Del is not present in gnomAD. G628Del 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 G628Del around 44% (4/11).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
None	None	None	None	97

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
30036649	2018	1	0	1
LITERATURE, COHORT, AND GNOMAD:	-	1	0	1	-
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
628	0	G628A, G628Del, G628S, G628R, G628V, G628D,
629	4	N629D, N629K, N629K, N629T, N629S, N629I,
630	5	V630T, V630I, V630A,
627	6	F627X, F627fsX, F627L, F627L, F627L,
631	6	S631F,
626	6	G626S, G626A, G626V,
628	6	G628A, G628Del, G628S, G628R, G628V, G628D,
628	6	G628A, G628Del, G628S, G628R, G628V, G628D,
627	7	F627X, F627fsX, F627L, F627L, F627L,
631	7	S631F,
629	8	N629D, N629K, N629K, N629T, N629S, N629I,
632	8	P632S, P632A,
626	8	G626S, G626A, G626V,
626	8	G626S, G626A, G626V,
616	9	Y616S,
628	9	G628A, G628Del, G628S, G628R, G628V, G628D,
617	9	F617L, F617V, F617L, F617L,
632	9	P632S, P632A,
620	9	S620I, S620G,
630	9	V630T, V630I, V630A,
625	10	V625E,
633	10	N633I, N633D, N633S,
592	10	Q592X,
629	10	N629D, N629K, N629K, N629T, N629S, N629I,
588	10	N588D, N588K, N588K,
626	10	G626S, G626A, G626V,
627	10	F627X, F627fsX, F627L, F627L, F627L,
625	10	V625E,
613	11	T613L, T613M, T613A, T613K,
630	11	V630T, V630I, V630A,
627	11	F627X, F627fsX, F627L, F627L, F627L,
638	11	K638Del, K638D, K638E, K638R,
621	11	S621R, S621R, S621R, S621N,
633	11	N633I, N633D, N633S,
589	12	L589P,
585	12	W585C, W585C,
625	12	V625E,
629	12	N629D, N629K, N629K, N629T, N629S, N629I,
631	12	S631F,
641	12	S641P, S641F,
616	12	Y616S,
617	12	F617L, F617V, F617L, F617L,
625	13	V625E,
620	13	S620I, S620G,
621	13	S621R, S621R, S621R, S621N,
614	13	A614V, A614T,
631	13	S631F,
588	13	N588D, N588K, N588K,
620	13	S620I, S620G,
624	13	S624R, S624R, S624R, S624N,
592	13	Q592X,
641	13	S641P, S641F,
618	13	T618S, T618S,
568	13	W568C, W568C,
584	13	G584C, G584R, G584S,
637	13	E637G, E637K, E637X,
637	13	E637G, E637K, E637X,
645	13	M645I, M645L, M645V, M645I, M645L, M645I, M645R,
638	14	K638Del, K638D, K638E, K638R,
624	14	S624R, S624R, S624R, S624N,
630	14	V630T, V630I, V630A,
634	14	T634S, T634S, T634P, T634A, T634I,
591	14	D591N, D591H,
593	14	I593R, I593X, I593K, I593T, I593V,
623	14	T623I,
584	14	G584C, G584R, G584S,
616	14	Y616S,
624	14	S624R, S624R, S624R, S624N,
619	14
586	14	L586M,
615	14	L615F, L615V,
642	14	I642V, I642Del,
592	14	Q592X,
612	14	V612L, V612A, V612L,
590	14	G590V, G590D,
617	15	F617L, F617V, F617L, F617L,
585	15	W585C, W585C,
632	15	P632S, P632A,
645	15	M645I, M645L, M645V, M645I, M645L, M645I, M645R,
634	15	T634S, T634S, T634P, T634A, T634I,
588	15	N588D, N588K, N588K,
624	15	S624R, S624R, S624R, S624N,