We estimate the penetrance of LQTS for KCNH2 A89V is 13%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. A89V is present in 1 alleles in gnomAD. A89V has not been functionally characterized. 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 A89V around 13% (1/11).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-2.265	0.555	-1	0.514	13

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:	-	1	1	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.

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
89	0	A89V, A89G,
88	3
90	4	E90K,
114	6	P114S,
85	6	A85P, A85V,
87	7	L87P,
122	7
86	7	L86R,
92	8	R92C, R92L,
116	8	K116Q,
91	9
112	9	V112M,
125	9
113	9	V113Del,
121	9	A121fsX,
115	10	V115M,
84	10
120	11
83	11	A83P, A83fsX,
123	11
34	12	A34T,
82	12	I82T, I82dup, I82Del, I82Ins,
124	12	M124T, M124R,
126	12
111	13	D111V,
117	13
81	13	Q81H, Q81E, Q81X, Q81H, Q81P,
127	13
93	14	K93R, K93X,
32	14	A32T,
39	14	C39R, C39X,
119	14	D119H, D119G,
94	14	V94L, V94L, V94A,
64	14	C64R, C64Y,
33	14	N33T,
110	14	V110A,
80	15	A80P,
35	15	R35W,