KCNQ1 Variant S276F Detail

We estimate the penetrance of LQTS for KCNQ1 S276F is 66%. We are unaware of any observations of this variant in individuals. S276F is not present in gnomAD. S276F 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S276F around 66% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.37 1.0 6 0.809 69
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 4 6 -
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.

S276F has 50 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
276 0 S276del,
277 4 S277L, S277del, S277P, S277W,
279 5 F279I,
272 6 G272D, G272S, G272V,
280 6 V280A, V280E,
275 6 F275del,
278 6 Y278H,
274 7 I274V,
299 9
271 10
282 10 L282P,
269 10 G269D, G269S, G269del,
235 10 I235N,
281 10 Y281C,
283 11 A283G, A283T,
232 11
284 11 E284K,
296 12 F296S, F296L, F296L, F296L,
324 12
339 13 F339del, F339S,
268 13 I268V, I268S,
330 13
307 13 V307L, V307L,
236 13 L236Q, L236R,
231 13 R231C, R231H, R231S,
238 13 M238V, M238L, M238L,
329 13 A329T,
322 13 T322M, T322A, T322K,
333 14
311 14 T311A, T311I,
298 14 S298I, S298N,
308 14 V308F,
331 14
334 14 V334A,
239 14
285 14
304 14 W304R, W304R,
137 14 L137F, L137P,
306 14 G306V, G306R, G306R,
267 15 Y267C,
332 15
141 15 V141M,
295 15
315 15 Y315C, Y315S, Y315N, Y315H, Y315F,
310 15 V310I,
228 15
234 15 Q234H, Q234H,
229 15 G229D,
328 15 I328del,
327 15 T327A, T327S, T327S,