KCNQ1 Variant F232C Detail

We estimate the penetrance of LQTS for KCNQ1 F232C is 50%. We are unaware of any observations of this variant in individuals. F232C is not present in gnomAD. F232C 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 F232C around 50% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.69 0.997 2 0.956 56
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.

F232C has 60 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
232 0
233 5 L233P,
229 5 G229D,
236 5 L236Q, L236R,
235 5 I235N,
278 6 Y278H,
275 7 F275del,
234 7 Q234H, Q234H,
230 7
231 8 R231C, R231H, R231S,
279 8 F279I,
228 9
205 9 V205M,
237 9
282 10 L282P,
225 10 S225L, S225del,
208 10 A208V,
204 10 I204M, I204F,
274 10 I274V,
239 10
226 10 A226V,
209 11 S209P,
238 11 M238V, M238L, M238L,
201 11 I201del,
137 11 L137F, L137P,
277 11 S277L, S277del, S277P, S277W,
276 11 S276del,
299 11
227 11
140 11 S140G, S140R, S140R, S140R,
212 12
271 12
240 12 H240R, H240P,
272 12 G272D, G272S, G272V,
281 12 Y281C,
136 13
206 13 V206L,
280 13 V280A, V280E,
207 13 V207M, V207L, V207L, V207L, V207L, V207del,
160 13 E160del, E160K, E160V,
224 13 T224M,
133 13 V133I,
202 13 D202N, D202H,
332 14
211 14
283 14 A283G, A283T,
273 14 L273F, L273V, L273R,
141 14 V141M,
328 14 I328del,
144 14 T144A,
303 14 L303P,
221 14
203 14 L203P,
213 14
285 15
200 15
302 15 A302V, A302E, A302T,
222 15
164 15
143 15 S143F, S143P, S143Y,