We estimate the penetrance of LQTS for KCNH2 V625E is 46%. This variant was found in a total of 2 carriers in 1 papers or gnomAD (version 4), 2 had LQTS. V625E 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. V625E 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 V625E around 46% (5/12).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-5.801	1.0	-3	0.978	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
19127321	2008	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
625	0	V625E,
626	4	G626S, G626A, G626V,
624	4	S624R, S624R, S624R, S624N,
624	5	S624R, S624R, S624R, S624N,
620	5	S620I, S620G,
626	5	G626S, G626A, G626V,
627	5	F627X, F627fsX, F627L, F627L, F627L,
623	6	T623I,
625	6	V625E,
625	6	V625E,
621	6	S621R, S621R, S621R, S621N,
645	7	M645I, M645L, M645V, M645I, M645L, M645I, M645R,
621	7	S621R, S621R, S621R, S621N,
626	7	G626S, G626A, G626V,
620	7	S620I, S620G,
624	8	S624R, S624R, S624R, S624N,
624	8	S624R, S624R, S624R, S624N,
626	8	G626S, G626A, G626V,
625	8	V625E,
627	8	F627X, F627fsX, F627L, F627L, F627L,
623	8	T623I,
622	9	L622F,
627	9	F627X, F627fsX, F627L, F627L, F627L,
616	9	Y616S,
641	9	S641P, S641F,
619	9
622	9	L622F,
628	10	G628A, G628Del, G628S, G628R, G628V, G628D,
617	10	F617L, F617V, F617L, F617L,
644	10	V644I, V644F,
623	10	T623I,
620	10	S620I, S620G,
618	10	T618S, T618S,
617	10	F617L, F617V, F617L, F617L,
628	10	G628A, G628Del, G628S, G628R, G628V, G628D,
648	11	G648A,
649	11
642	11	I642V, I642Del,
652	11	Y652X,
645	11	M645I, M645L, M645V, M645I, M645L, M645I, M645R,
630	11	V630T, V630I, V630A,
627	11	F627X, F627fsX, F627L, F627L, F627L,
629	11	N629D, N629K, N629K, N629T, N629S, N629I,
632	11	P632S, P632A,
631	12	S631F,
652	12	Y652X,
618	12	T618S, T618S,
628	12	G628A, G628Del, G628S, G628R, G628V, G628D,
623	12	T623I,
621	12	S621R, S621R, S621R, S621N,
620	12	S620I, S620G,
645	12	M645I, M645L, M645V, M645I, M645L, M645I, M645R,
648	12	G648A,
630	12	V630T, V630I, V630A,
646	12
621	12	S621R, S621R, S621R, S621N,
644	12	V644I, V644F,
641	13	S641P, S641F,
631	13	S631F,
628	13	G628A, G628Del, G628S, G628R, G628V, G628D,
619	13
616	13	Y616S,
638	13	K638Del, K638D, K638E, K638R,
615	13	L615F, L615V,
649	13
643	13
647	13
629	13	N629D, N629K, N629K, N629T, N629S, N629I,
640	13	F640Del, F640L, F640V, F640L, F640L,
652	14	Y652X,
557	14
629	14	N629D, N629K, N629K, N629T, N629S, N629I,
632	14	P632S, P632A,
616	14	Y616S,
622	14	L622F,
614	14	A614V, A614T,
561	14	A561T, A561P, A561V,
613	14	T613L, T613M, T613A, T613K,
652	14	Y652X,
622	14	L622F,
649	14
641	15	S641P, S641F,
645	15	M645I, M645L, M645V, M645I, M645L, M645I, M645R,
656	15	F656L, F656L, F656L,
619	15