We estimate the penetrance of LQTS for KCNH2 L87P is 37%. This variant was found in a total of 1 carriers in 1 papers or gnomAD (version 4), 1 had LQTS. L87P 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. L87P 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L87P around 37% (4/11).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-3.585	0.913	-3	0.849	84

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
12402336	2002	1	0	1
LITERATURE, COHORT, AND GNOMAD:	-	1	0	1	-
VARIANT FEATURES ALONE:	-	10	7	3	-

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
87	0	L87P,
88	5
86	5	L86R,
85	6	A85V, A85P,
84	7
83	7	A83fsX, A83P,
89	7	A89V, A89G,
122	9
90	9	E90K,
125	10
34	10	A34T,
82	10	I82T, I82dup, I82Ins, I82Del,
39	10	C39X, C39R,
92	10	R92L, R92C,
114	11	P114S,
80	11	A80P,
64	12	C64R, C64Y,
112	12	V112M,
81	12	Q81P, Q81E, Q81X, Q81H, Q81H,
121	12	A121fsX,
65	12	T65P,
38	12
35	12	R35W,
123	13
36	13	V36X,
32	13	A32T,
33	13	N33T,
116	13	K116Q,
79	13	A79Del, A79fsX, A79T, A79S,
124	14	M124R, M124T,
113	14	V113Del,
37	14
115	14	V115M,
120	14
91	14
63	14	P63H,
127	15
40	15
94	15	V94L, V94A, V94L,
126	15