KCNQ1 Variant F167L Detail

We estimate the penetrance of LQTS for KCNQ1 F167L is 38%. We are unaware of any observations of this variant in individuals. F167L is not present in gnomAD. F167L has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F167L around 38% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.53 0.999 -1 0.715 38
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 7 3 -
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.

F167L has 63 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
167 0
166 4 F166V,
163 5
164 5
168 6 G168R, G168R, G168R, G168R,
170 6
165 7 V165M,
237 7
206 7 V206L,
169 7 T169M, T169R,
202 8 D202N, D202H,
240 8 H240R, H240P,
129 8 V129I,
205 8 V205M,
171 9
162 9 V162M,
133 9 V133I,
132 9 I132L,
160 10 E160del, E160K, E160V,
174 10 R174H, R174C, R174L,
209 10 S209P,
125 10
203 10 L203P,
172 11 V172M, V172E,
161 11
159 11 M159del,
126 11 H126D,
233 11 L233P,
234 11 Q234H, Q234H,
173 11
136 11
130 12
114 12
207 12 V207M, V207L, V207L, V207L, V207L, V207del,
128 12 A128del,
241 12 V241F, V241I, V241G,
201 12 I201del,
236 12 L236Q, L236R,
243 12 R243H, R243C, R243P, R243S,
204 12 I204M, I204F,
199 12 S199A,
208 12 A208V,
210 12 M210I, M210I, M210I,
239 12
198 13 I198V, I198T,
238 13 M238V, M238L, M238L,
213 13
230 13
175 13 L175I,
131 13
134 14 L134P,
158 14
115 14 E115A, E115G,
135 14
137 14 L137F, L137P,
235 14 I235N,
113 14
200 14
156 14
212 15
242 15 D242N, D242Y,
176 15
127 15 F127L, F127L, F127L,