KCNQ1 Variant F130L Detail

We estimate the penetrance of LQTS for KCNQ1 F130L is 43%. We are unaware of any observations of this variant in individuals. F130L is not present in gnomAD. F130L 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F130L around 43% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.04 0.9 1 0.857 46
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 6 4 -
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.

F130L 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
130 0
133 5 V133I,
134 5 L134P,
131 5
241 6 V241F, V241I, V241G,
129 6 V129I,
238 6 M238V, M238L, M238L,
127 7 F127L, F127L, F127L,
128 7 A128del,
132 7 I132L,
126 8 H126D,
240 9 H240R, H240P,
135 9
137 9 L137F, L137P,
239 10
267 10 Y267C,
237 10
136 10
242 10 D242N, D242Y,
123 10
125 11
243 11 R243H, R243C, R243P, R243S,
124 11
235 11 I235N,
271 11
167 12
234 12 Q234H, Q234H,
138 12
236 12 L236Q, L236R,
163 12
274 13 I274V,
270 13 F270S,
166 13 F166V,
247 13 T247I,
170 14
139 14
122 14 C122Y,
248 14 W248C, W248C, W248R, W248R,
202 14 D202N, D202H,
268 14 I268V, I268S,
159 14 M159del,
117 14 P117L,
198 14 I198V, I198T,
263 14
114 14
233 14 L233P,
140 15 S140G, S140R, S140R, S140R,
275 15 F275del,
245 15 G245V,
205 15 V205M,
120 15 W120C, W120C,
246 15
264 15
266 15 L266P,
201 15 I201del,