KCNQ1 Variant L114F Detail

We estimate the penetrance of LQTS for KCNQ1 L114F is 76%. We are unaware of any observations of this variant in individuals. L114F is not present in gnomAD. L114F 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 L114F around 76% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.08 0.939 3 0.717 79
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.

L114F has 55 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
114 0
174 4 R174H, R174C, R174L,
113 5
115 5 E115A, E115G,
110 6 V110I,
111 6 Y111C,
170 7
112 7
126 7 H126D,
173 7
117 7 P117L,
177 8 S177F,
125 8
122 8 C122Y,
243 8 R243H, R243C, R243P, R243S,
116 9
108 9 G108S,
107 10 Q107H, Q107H,
171 10
178 10 A178T, A178del,
175 10 L175I,
244 10
172 11 V172M, V172E,
121 11
119 11 G119R, G119V,
176 11
129 11 V129I,
169 11 T169M, T169R,
193 11 F193L, F193L, F193L,
109 11 R109C, R109L,
180 11
166 11 F166V,
118 11
241 11 V241F, V241I, V241G,
167 12
202 12 D202N, D202H,
240 12 H240R, H240P,
198 12 I198V, I198T,
168 12 G168R, G168R, G168R, G168R,
106 12
199 12 S199A,
123 12
181 12 R181C,
124 12
179 13 G179S,
242 13 D242N, D242Y,
128 13 A128del,
196 13
184 13 Y184S, Y184C, Y184D, Y184H,
190 14 R190W, R190Q, R190L,
245 14 G245V,
127 14 F127L, F127L, F127L,
194 14 A194P, A194T,
130 14
120 15 W120C, W120C,