KCNQ1 Variant H240L Detail

We estimate the penetrance of LQTS for KCNQ1 H240L is 51%. We are unaware of any observations of this variant in individuals. H240L is not present in gnomAD. H240L 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 H240L around 51% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.59 0.996 -3 0.848 55
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 5 5 -
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.

H240L has 70 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
240 0 H240R, H240P,
239 5
202 5 D202N, D202H,
241 6 V241F, V241I, V241G,
237 6
201 7 I201del,
198 7 I198V, I198T,
243 7 R243H, R243C, R243P, R243S,
236 7 L236Q, L236R,
238 7 M238V, M238L, M238L,
242 8 D242N, D242Y,
167 8
205 8 V205M,
133 9 V133I,
199 9 S199A,
130 9
129 9 V129I,
170 10
235 10 I235N,
233 10 L233P,
204 10 I204M, I204F,
126 10 H126D,
174 10 R174H, R174C, R174L,
206 10 V206L,
248 10 W248C, W248C, W248R, W248R,
171 10
200 10
203 11 L203P,
234 11 Q234H, Q234H,
197 11 P197L,
245 11 G245V,
115 11 E115A, E115G,
271 11
267 11 Y267C,
244 11
168 11 G168R, G168R, G168R, G168R,
166 12 F166V,
196 12
163 12
114 12
132 12 I132L,
164 12
134 12 L134P,
232 12
137 12 L137F, L137P,
125 12
247 13 T247I,
136 13
275 13 F275del,
209 13 S209P,
128 13 A128del,
246 13
131 13
208 13 A208V,
207 14 V207M, V207L, V207L, V207L, V207L, V207del,
194 14 A194P, A194T,
268 14 I268V, I268S,
169 14 T169M, T169R,
127 14 F127L, F127L, F127L,
160 14 E160del, E160K, E160V,
274 14 I274V,
193 14 F193L, F193L, F193L,
117 14 P117L,
230 14
165 15 V165M,
172 15 V172M, V172E,
175 15 L175I,
173 15
135 15
113 15