We estimate the penetrance of LQTS for KCNH2 F627V is 36%. We are unaware of any observations of this variant in individuals. F627V is not present in gnomAD. We have tested the trafficking efficiency of this variant, 44% of WT with a standard error of 11%; 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. F627V 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 F627V around 36% (3/10).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-6.767	1.0	-1	0.94	94

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
627	0	F627fsX, F627L, F627X, F627L, F627L,
626	4	G626A, G626V, G626S,
626	5	G626A, G626V, G626S,
625	5	V625E,
628	6	G628V, G628R, G628D, G628Del, G628S, G628A,
620	6	S620G, S620I,
629	6	N629S, N629T, N629K, N629I, N629D, N629K,
616	6	Y616S,
631	6	S631F,
632	7	P632S, P632A,
628	7	G628V, G628R, G628D, G628Del, G628S, G628A,
621	7	S621R, S621N, S621R, S621R,
641	7	S641F, S641P,
630	8	V630A, V630T, V630I,
630	8	V630A, V630T, V630I,
620	8	S620G, S620I,
617	8	F617L, F617L, F617L, F617V,
645	8	M645I, M645L, M645R, M645L, M645V, M645I, M645I,
625	8	V625E,
627	9	F627fsX, F627L, F627X, F627L, F627L,
627	9	F627fsX, F627L, F627X, F627L, F627L,
626	9	G626A, G626V, G626S,
617	9	F617L, F617L, F617L, F617V,
638	9	K638E, K638R, K638D, K638Del,
624	9	S624R, S624R, S624N, S624R,
625	9	V625E,
626	9	G626A, G626V, G626S,
621	9	S621R, S621N, S621R, S621R,
624	9	S624R, S624R, S624N, S624R,
623	10	T623I,
631	10	S631F,
642	10	I642V, I642Del,
629	10	N629S, N629T, N629K, N629I, N629D, N629K,
633	10	N633D, N633I, N633S,
628	10	G628V, G628R, G628D, G628Del, G628S, G628A,
644	11	V644F, V644I,
619	11
637	11	E637G, E637K, E637X,
613	11	T613K, T613M, T613L, T613A,
628	11	G628V, G628R, G628D, G628Del, G628S, G628A,
625	11	V625E,
618	11	T618S, T618S,
618	11	T618S, T618S,
616	11	Y616S,
640	11	F640L, F640L, F640L, F640Del, F640V,
623	12	T623I,
622	12	L622F,
624	12	S624R, S624R, S624N, S624R,
568	12	W568C, W568C,
627	12	F627fsX, F627L, F627X, F627L, F627L,
624	12	S624R, S624R, S624N, S624R,
622	12	L622F,
615	12	L615F, L615V,
629	12	N629S, N629T, N629K, N629I, N629D, N629K,
614	12	A614T, A614V,
632	13	P632S, P632A,
639	13	I639N, I639F,
634	13	T634A, T634P, T634S, T634S, T634I,
585	13	W585C, W585C,
592	13	Q592X,
612	13	V612A, V612L, V612L,
643	13
620	13	S620G, S620I,
631	13	S631F,
648	14	G648A,
619	14
614	14	A614T, A614V,
645	14	M645I, M645L, M645R, M645L, M645V, M645I, M645I,
588	14	N588K, N588K, N588D,
641	14	S641F, S641P,
613	14	T613K, T613M, T613L, T613A,
646	14
632	14	P632S, P632A,
636	14
621	14	S621R, S621N, S621R, S621R,
645	14	M645I, M645L, M645R, M645L, M645V, M645I, M645I,
620	14	S620G, S620I,
584	14	G584R, G584S, G584C,
635	14	N635I,
649	14
589	14	L589P,
568	14	W568C, W568C,
585	14	W585C, W585C,
588	14	N588K, N588K, N588D,
629	15	N629S, N629T, N629K, N629I, N629D, N629K,
623	15	T623I,
644	15	V644F, V644I,
630	15	V630A, V630T, V630I,
616	15	Y616S,
564	15	L564L,
630	15	V630A, V630T, V630I,