We estimate the penetrance of LQTS for KCNH2 V122D is 15%. We are unaware of any observations of this variant in individuals. V122D is not present in gnomAD. We have tested the trafficking efficiency of this variant, 77% of WT with a standard error of 14%; 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. V122D 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 V122D around 15% (1/10).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-4.84	0.44	-4	0.935	39

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:	-	0	0	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
122	0
121	4	A121fsX,
123	4
116	6	K116Q,
34	6	A34T,
115	7	V115M,
124	7	M124R, M124T,
114	7	P114S,
125	7
120	7
89	7	A89V, A89G,
117	8
33	9	N33T,
35	9	R35W,
88	9
86	9	L86R,
87	9	L87P,
32	10	A32T,
119	10	D119G, D119H,
90	10	E90K,
113	10	V113Del,
39	11	C39X, C39R,
85	11	A85V, A85P,
126	11
36	11	V36X,
118	11	E118K, E118D, E118X, E118D,
112	12	V112M,
14	13
31	13	I31S,
795	13	V795I,
64	13	C64Y, C64R,
40	14
127	14
91	14
92	14	R92L, R92C,
15	14	L15V,
794	14	V794I, V794D,
83	14	A83fsX, A83P,
12	14	N12D,
42	15	I42N,
37	15
38	15
84	15
18	15	I18M,