KCNQ1 Variant F157L Detail

We estimate the penetrance of LQTS for KCNQ1 F157L is 78%. We are unaware of any observations of this variant in individuals. F157L is not present in gnomAD. F157L 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 F157L around 78% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.66 0.019 -1 0.675 90
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.

F157L has 45 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
157 0 F157C,
154 5
161 6
213 6
156 7
217 7
160 7 E160del, E160K, E160V,
216 7 G216R,
153 7 T153M,
158 7
155 8
159 8 M159del,
152 9
162 9 V162M,
222 9
214 10 C214Y,
212 10
226 10 A226V,
230 10
218 10
215 11 V215M, V215G, V215L, V215L,
209 11 S209P,
164 11
163 11
151 12
149 12
219 12 G219E,
227 12
143 13 S143F, S143P, S143Y,
136 13
210 13 M210I, M210I, M210I,
165 13 V165M,
150 13 A150T,
211 13
139 13
234 13 Q234H, Q234H,
140 13 S140G, S140R, S140R, S140R,
225 13 S225L, S225del,
221 14
223 14
229 14 G229D,
231 14 R231C, R231H, R231S,
208 14 A208V,
233 14 L233P,
237 15