We estimate the penetrance of LQTS for KCNH2 L799splice is %. We are unaware of any observations of this variant in individuals. L799splice is not present in gnomAD. L799splice has not been functionally characterized. This residue is located in a None region for LQT2.

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

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	NA	NA	-

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
799	0	L799sp,
800	4
787	5
798	5	I798fsX,
803	5	D803X, D803Y,
797	6	A797T,
786	7
782	7	I782fsX, I782N,
859	7	T859R, T859M,
788	7	E788D, E788D, E788K,
789	7
805	7	F805C, F805S,
860	8
56	8	R56Q,
43	8	Y43C, Y43D,
785	8	G785D, G785S, G785fsX,
804	8
801	9	K801T,
42	9	I42N,
44	9	C44W, C44F, C44X,
60	9	M60T,
802	9
822	9	V822M, V822L, V822L,
796	10	V796L, V796L, V796Del,
824	10
828	10
825	10
783	10	S783P,
780	11
830	11
858	11	I858V, I858T,
781	11
795	11	V795I,
806	11	G806R, G806R,
790	11
826	11	T826A, T826I,
57	11	A57P,
16	12	D16A,
19	12	I19F,
15	12	L15V,
41	12	V41A,
823	12	R823W, R823T, R823Q, R823fsX,
31	12	I31S,
45	12	N45K, N45D, N45K,
61	12	Q61R,
769	12
862	12	L862P,
829	12	D829E, D829A, D829E,
46	13	D46E, D46Y, D46E,
763	13
59	13
784	13	R784G, R784Q, R784W,
820	13	G820R, G820R,
861	13	N861I, N861H,
770	13
55	13	S55L,
779	13
821	13	D821E, D821E,
12	13	N12D,
831	13
857	13	E857X,
30	14	I30Del, I30T,
40	14
29	14	F29S, F29L, F29L, F29L, F29V,
819	14	N819K, N819K,
13	14	T13N,
32	14	A32T,
767	14	D767X,
49	15	C49G, C49R,
794	15	V794D, V794I,
768	15
761	15
766	15
791	15	R791Q, R791W,
765	15
740	15	C740W, C740G,
764	15
736	15