KCNQ1 Variant F166S Detail

We estimate the penetrance of LQTS for KCNQ1 F166S is 15%. We are unaware of any observations of this variant in individuals. F166S is not present in gnomAD. F166S 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F166S around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.65 0.996 -4 0.914 11
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 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.

F166S has 50 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
166 0 F166V,
167 4
163 6
170 6
169 6 T169M, T169R,
165 6 V165M,
168 6 G168R, G168R, G168R, G168R,
164 7
162 7 V162M,
129 8 V129I,
125 9
132 9 I132L,
173 10
172 11 V172M, V172E,
174 11 R174H, R174C, R174L,
206 11 V206L,
171 11
161 11
128 11 A128del,
159 11 M159del,
237 11
126 11 H126D,
160 11 E160del, E160K, E160V,
133 11 V133I,
114 11
240 12 H240R, H240P,
202 12 D202N, D202H,
158 12
205 13 V205M,
113 13
209 13 S209P,
136 13
130 13
131 13
203 14 L203P,
241 14 V241F, V241I, V241G,
176 14
243 14 R243H, R243C, R243P, R243S,
175 14 L175I,
210 14 M210I, M210I, M210I,
234 14 Q234H, Q234H,
124 14
135 14
110 14 V110I,
127 15 F127L, F127L, F127L,
207 15 V207M, V207L, V207L, V207L, V207L, V207del,
122 15 C122Y,
115 15 E115A, E115G,
233 15 L233P,
213 15