We estimate the penetrance of LQTS for KCNH2 M124K is 22%. We are unaware of any observations of this variant in individuals. M124K is not present in gnomAD. We have tested the trafficking efficiency of this variant, 59% of WT with a standard error of 16%; 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. M124K 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 M124K around 22% (2/10).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-4.37	0.09	-4	0.919	66

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	8	2	-

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
124	0	M124T, M124R,
123	4
32	5	A32T,
33	5	N33T,
125	5
115	6	V115M,
31	6	I31S,
34	6	A34T,
122	7
126	7
15	8	L15V,
114	8	P114S,
795	8	V795I,
14	8
42	8	I42N,
35	9	R35W,
116	9	K116Q,
121	9	A121fsX,
39	9	C39R, C39X,
113	10	V113Del,
40	10
12	10	N12D,
18	10	I18M,
36	10	V36X,
117	10
30	10	I30Del, I30T,
41	10	V41A,
127	10
796	11	V796L, V796Del, V796L,
794	11	V794D, V794I,
86	11	L86R,
64	11	C64R, C64Y,
798	11	I798fsX,
43	11	Y43C, Y43D,
112	12	V112M,
797	12	A797T,
89	12	A89V, A89G,
29	12	F29L, F29L, F29S, F29V, F29L,
19	12	I19F,
788	12	E788D, E788D, E788K,
120	12
13	12	T13N,
11	13	Q11H, Q11L, Q11H,
17	13
90	13	E90K,
16	13	D16A,
85	13	A85V, A85P,
87	14	L87P,
790	14
22	14	F22Y, F22S,
793	14	D793N,
38	14
88	14
118	14	E118D, E118X, E118D, E118K,
119	14	D119G, D119H,
128	14	N128S,
111	14	D111V,
63	14	P63H,
44	14	C44X, C44F, C44W,
60	14	M60T,
789	14
37	14
65	15	T65P,