We estimate the penetrance of LQTS for KCNQ1 R109H is 13%. We are unaware of any observations of this variant in individuals. R109H is not present in gnomAD. R109H has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R109H around 13% (1/10).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-2.27	0.998	-2	0.771	5

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	LQT1	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. This results from the fact that the functional K_V7.1 channel 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
109	0	R109C, R109L,
106	5
108	5	G108S,
105	6
110	6	V110I,
107	8	Q107H, Q107H,
112	8
113	9
104	9	T104A, T104I,
180	10
111	10	Y111C,
177	11	S177F,
121	11
122	11	C122Y,
114	11
119	12	G119R, G119V,
116	12
118	12
117	12	P117L,
179	13	G179S,
173	13
115	13	E115A, E115G,
178	13	A178T, A178del,
181	14	R181C,
176	14
174	14	R174H, R174C, R174L,
125	15