We estimate the penetrance of LQTS for KCNH2 A34T is 13%. This variant was found in a total of 1 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. A34T is present in 1 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 84% of WT with a standard error of 13%; 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. A34T 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A34T around 13% (1/11).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-2.454	1.0	-1	0.918	66

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
34	0	A34T,
35	4	R35W,
33	4	N33T,
36	5	V36X,
39	6	C39R, C39X,
123	6
122	6
124	6	M124T, M124R,
32	7	A32T,
125	7
40	8
37	9
86	9	L86R,
38	9
794	9	V794D, V794I,
121	9	A121fsX,
795	9	V795I,
87	10	L87P,
64	10	C64R, C64Y,
115	11	V115M,
42	11	I42N,
31	11	I31S,
796	11	V796Del, V796L, V796L,
114	11	P114S,
41	11	V41A,
116	12	K116Q,
89	12	A89V, A89G,
63	12	P63H,
126	12
88	12
117	12
85	12	A85P, A85V,
120	13
793	13	D793N,
792	13
83	13	A83P, A83fsX,
65	13	T65P,
791	13	R791Q, R791W,
127	13
797	14	A797T,
15	14	L15V,
12	14	N12D,
30	14	I30Del, I30T,
113	14	V113Del,
14	14
112	14	V112M,
790	14
90	14	E90K,
61	14	Q61R,
119	15	D119G, D119H,
798	15	I798fsX,