KCNQ1 Variant F113C Detail

We estimate the penetrance of LQTS for KCNQ1 F113C is 73%. We are unaware of any observations of this variant in individuals. F113C is not present in gnomAD. F113C has not been functionally characterized. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F113C around 73% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.89 0.201 3 0.708 75
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).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT1 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
VARIANT FEATURES ALONE: - 10 3 7 -
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.

F113C has 43 previously observed neighbors within 15 angstroms

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 KV7.1 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
113 0
122 4 C122Y,
114 5
110 6 V110I,
125 6
121 7
112 7
117 7 P117L,
126 7 H126D,
119 8 G119R, G119V,
115 8 E115A, E115G,
111 8 Y111C,
174 9 R174H, R174C, R174L,
109 9 R109C, R109L,
108 9 G108S,
118 9
170 9
124 9
116 10
173 10
123 10
177 10 S177F,
107 11 Q107H, Q107H,
106 11
243 11 R243H, R243C, R243P, R243S,
120 11 W120C, W120C,
129 11 V129I,
128 12 A128del,
166 13 F166V,
180 13
127 13 F127L, F127L, F127L,
241 13 V241F, V241I, V241G,
244 13
178 13 A178T, A178del,
169 13 T169M, T169R,
176 14
172 14 V172M, V172E,
167 14
175 14 L175I,
171 14
105 15
181 15 R181C,
240 15 H240R, H240P,