We estimate the penetrance of LQTS for KCNH2 L127R is 26%. We are unaware of any observations of this variant in individuals. L127R is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 0%; 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. L127R 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 L127R around 26% (2/10).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-4.346	0.996	-4	0.948	72

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
127	0
30	5	I30Del, I30T,
126	5
128	6	N128S,
112	6	V112M,
129	6	F129C,
111	6	D111V,
110	7	V110A,
29	7	F29L, F29L, F29L, F29V, F29S,
125	7
113	7	V113Del,
31	7	I31S,
64	8	C64Y, C64R,
32	8	A32T,
114	9	P114S,
28	9	K28E,
48	9
82	9	I82dup, I82Del, I82T, I82Ins,
66	10	C66G, C66R, C66Y,
65	10	T65P,
41	10	V41A,
86	10	L86R,
109	10	L109P, L109Q, L109X,
124	10	M124R, M124T,
94	11	V94L, V94A, V94L,
43	11	Y43D, Y43C,
85	11	A85V, A85P,
22	11	F22S, F22Y,
27	11	R27X, R27P,
108	11	C108Y,
45	11	N45K, N45D, N45K,
93	11	K93R, K93X,
44	11	C44W, C44X, C44F,
39	11	C39X, C39R,
91	11
42	11	I42N,
115	11	V115M,
130	12	E130K,
92	12	R92L, R92C,
98	12
40	12
63	12	P63H,
90	12	E90K,
69	12	L69Del, L69P,
18	12	I18M,
83	12	A83fsX, A83P,
59	12
96	12	I96T, I96V,
33	12	N33T,
47	13	G47V, G47C,
19	13	I19F,
51	13
89	13	A89V, A89G,
34	13	A34T,
52	14	C52W,
60	14	M60T,
122	14
68	14	F68L, F68V, F68L, F68L,
79	14	A79fsX, A79S, A79Del, A79T,
123	14
15	14	L15V,
49	14	C49R, C49G,
81	14	Q81H, Q81X, Q81H, Q81P, Q81E,
95	14	E95G, E95K,
25	14	Q25P,
70	14	H70Q, H70R, H70Q,
798	14	I798fsX,
131	14	V131L, V131L, V131fsX,
62	14	R62Q,
67	14
87	15	L87P,
26	15	S26I,
106	15	F106L, F106L, F106V, F106L,
88	15
21	15
97	15
80	15	A80P,
78	15	A78P, A78T,
84	15