We estimate the penetrance of LQTS for KCNH2 G626A is 36%. This variant was found in a total of 2 carriers in 1 papers or gnomAD (version 4), 2 had LQTS. G626A is not present in gnomAD. We have tested the trafficking efficiency of this variant, 117% of WT with a standard error of 23%; 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. G626A 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 G626A around 36% (5/12).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-5.801	1.0	0	0.951	91

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
Italy Cohort	2020	2	0	2
LITERATURE, COHORT, AND GNOMAD:	-	2	0	2	-
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
626	0	G626S, G626A, G626V,
625	4	V625E,
627	4	F627X, F627fsX, F627L, F627L, F627L,
626	5	G626S, G626A, G626V,
626	5	G626S, G626A, G626V,
620	5	S620I, S620G,
625	5	V625E,
627	5	F627X, F627fsX, F627L, F627L, F627L,
628	6	G628A, G628Del, G628S, G628R, G628V, G628D,
624	7	S624R, S624R, S624R, S624N,
621	7	S621R, S621R, S621R, S621N,
626	7	G626S, G626A, G626V,
625	7	V625E,
624	8	S624R, S624R, S624R, S624N,
625	8	V625E,
617	8	F617L, F617V, F617L, F617L,
628	8	G628A, G628Del, G628S, G628R, G628V, G628D,
623	8	T623I,
630	8	V630T, V630I, V630A,
628	8	G628A, G628Del, G628S, G628R, G628V, G628D,
624	9	S624R, S624R, S624R, S624N,
616	9	Y616S,
627	9	F627X, F627fsX, F627L, F627L, F627L,
629	9	N629D, N629K, N629K, N629T, N629S, N629I,
621	9	S621R, S621R, S621R, S621N,
620	9	S620I, S620G,
620	9	S620I, S620G,
631	9	S631F,
645	9	M645I, M645L, M645V, M645I, M645L, M645I, M645R,
627	9	F627X, F627fsX, F627L, F627L, F627L,
624	9	S624R, S624R, S624R, S624N,
631	10	S631F,
628	10	G628A, G628Del, G628S, G628R, G628V, G628D,
622	10	L622F,
629	10	N629D, N629K, N629K, N629T, N629S, N629I,
641	10	S641P, S641F,
632	10	P632S, P632A,
618	11	T618S, T618S,
645	11	M645I, M645L, M645V, M645I, M645L, M645I, M645R,
623	11	T623I,
619	11
632	11	P632S, P632A,
641	11	S641P, S641F,
630	11	V630T, V630I, V630A,
623	11	T623I,
617	11	F617L, F617V, F617L, F617L,
621	11	S621R, S621R, S621R, S621N,
616	12	Y616S,
629	12	N629D, N629K, N629K, N629T, N629S, N629I,
620	12	S620I, S620G,
630	12	V630T, V630I, V630A,
644	12	V644I, V644F,
642	12	I642V, I642Del,
638	12	K638Del, K638D, K638E, K638R,
622	12	L622F,
621	13	S621R, S621R, S621R, S621N,
644	13	V644I, V644F,
613	13	T613L, T613M, T613A, T613K,
617	13	F617L, F617V, F617L, F617L,
623	13	T623I,
631	13	S631F,
629	13	N629D, N629K, N629K, N629T, N629S, N629I,
614	13	A614V, A614T,
616	13	Y616S,
615	13	L615F, L615V,
648	13	G648A,
618	14	T618S, T618S,
631	14	S631F,
645	14	M645I, M645L, M645V, M645I, M645L, M645I, M645R,
652	14	Y652X,
633	14	N633I, N633D, N633S,
568	14	W568C, W568C,
648	14	G648A,
622	14	L622F,
642	14	I642V, I642Del,
630	14	V630T, V630I, V630A,
619	14
649	14
638	14	K638Del, K638D, K638E, K638R,
640	14	F640Del, F640L, F640V, F640L, F640L,
633	15	N633I, N633D, N633S,
645	15	M645I, M645L, M645V, M645I, M645L, M645I, M645R,
649	15
619	15
640	15	F640Del, F640L, F640V, F640L, F640L,
585	15	W585C, W585C,
646	15
637	15	E637G, E637K, E637X,
632	15	P632S, P632A,
637	15	E637G, E637K, E637X,
618	15	T618S, T618S,
652	15	Y652X,