We estimate the penetrance of LQTS for KCNH2 E90K is 11%. This variant was found in a total of 3 carriers in 1 papers or gnomAD, 0 had LQTS. E90K is present in 3 alleles in gnomAD. E90K 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E90K around 11% (1/13).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-2.382	0.409	1	0.698	17

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
29752375	2018	1	0		SIDS
LITERATURE, COHORT, AND GNOMAD:	-	3	3	0	-
VARIANT FEATURES ALONE:	-	10	9	1	-

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)
29752375	HEK293		111	4.0	None	None	1.0

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)
29752375	HEK293		100	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
90	0	E90K,
89	4	A89G, A89V,
92	5	R92L, R92C,
91	5
88	6
114	6	P114S,
85	6	A85V, A85P,
112	7	V112M,
113	7	V113Del,
86	8	L86R,
87	9	L87P,
125	10
111	10	D111V,
116	10	K116Q,
122	10
93	10	K93R, K93X,
115	10	V115M,
84	10
82	11	I82dup, I82T, I82Ins, I82Del,
126	11
83	11	A83P, A83fsX,
94	11	V94L, V94A, V94L,
81	12	Q81H, Q81E, Q81X, Q81H, Q81P,
110	12	V110A,
127	12
121	12	A121fsX,
124	13	M124T, M124R,
123	13
120	13
128	14	N128S,
80	14	A80P,
34	14	A34T,
32	14	A32T,
64	14	C64Y, C64R,
109	15	L109X, L109Q, L109P,
117	15