We estimate the penetrance of LQTS for KCNH2 V115M is 19%. This variant was found in a total of 7 carriers in 2 papers or gnomAD, 1 had LQTS. V115M is present in 4 alleles in gnomAD. V115M has been functionally characterized in 1 papers. This residue is located in a Mild_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 V115M around 19% (3/17).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-2.206	0.468	-1	0.867	28

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
21216356	2011	1	0	1
Japan Cohort	2020	2	2	0
LITERATURE, COHORT, AND GNOMAD:	-	7	6	1	-
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.

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V_0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID	Cell Type	S.S Peak (%WT)	Peak Tail IKr (%WT)	V1/2 Act.	V1/2 Inact.	Recov. Inact.	Deactivation (%WT)
25417810	HEK293		75	-0.9	None	None	1.033532934

Functional parameters are the same as defined above.

PubMed ID	Cell Type	S.S Peak (%WT)	Peak Tail IKr (%WT)	V1/2 Act.	V1/2 Inact.	Deactivation (%WT)
25417810	HEK293			None	None	None

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
115	0	V115M,
114	5	P114S,
116	5	K116Q,
124	6	M124T, M124R,
123	6
122	7
113	7	V113Del,
126	7
125	7
117	8
121	8	A121fsX,
14	8
18	9	I18M,
89	10	A89V, A89G,
15	10	L15V,
32	10	A32T,
120	10
90	10	E90K,
31	10	I31S,
112	10	V112M,
34	11	A34T,
33	11	N33T,
118	11	E118X, E118K, E118D, E118D,
91	11
127	11
119	12	D119G, D119H,
86	12	L86R,
17	12
111	12	D111V,
12	12	N12D,
88	12
22	13	F22Y, F22S,
85	13	A85V, A85P,
30	13	I30Del, I30T,
19	13	I19F,
21	13
35	13	R35W,
29	13	F29L, F29V, F29S, F29L, F29L,
795	13	V795I,
13	13	T13N,
128	13	N128S,
42	14	I42N,
39	14	C39R, C39X,
92	14	R92C, R92L,
87	14	L87P,
16	14	D16A,
64	14	C64Y, C64R,
11	14	Q11H, Q11L, Q11H,
43	15	Y43D, Y43C,
36	15	V36X,