KCNQ1 Variant F279L Detail

We estimate the penetrance of LQTS for KCNQ1 F279L is 44%. We are unaware of any observations of this variant in individuals. F279L is not present in gnomAD. F279L 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 F279L around 44% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.61 0.197 3 0.749 53
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.

F279L has 48 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
279 0 F279I,
278 4 Y278H,
276 5 S276del,
282 6 L282P,
328 6 I328del,
280 6 V280A, V280E,
275 6 F275del,
277 7 S277L, S277del, S277P, S277W,
332 7
283 8 A283G, A283T,
232 8
325 8 G325R, G325R, G325E, G325W,
281 9 Y281C,
324 9
274 9 I274V,
272 9 G272D, G272S, G272V,
235 10 I235N,
299 10
273 10 L273F, L273V, L273R,
284 10 E284K,
302 10 A302V, A302E, A302T,
228 11
231 11 R231C, R231H, R231S,
229 11 G229D,
236 12 L236Q, L236R,
322 12 T322M, T322A, T322K,
285 12
333 12
296 12 F296S, F296L, F296L, F296L,
271 12
335 12 F335L, F335L, F335L,
320 12 P320H, P320A, P320S,
233 13 L233P,
323 13
336 13 A336S,
234 14 Q234H, Q234H,
309 14 T309I, T309R,
286 14
269 14 G269D, G269S, G269del,
230 14
225 14 S225L, S225del,
298 14 S298I, S298N,
227 15
239 15
238 15 M238V, M238L, M238L,
287 15 A287E, A287T, A287S,
297 15 G297S, G297D, G297R,
140 15 S140G, S140R, S140R, S140R,