KCNQ1 Variant F275S Detail

We estimate the penetrance of LQTS for KCNQ1 F275S is 64%. We are unaware of any observations of this variant in individuals. F275S is not present in gnomAD. F275S has been functionally characterized in 1 papers. 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 F275S around 64% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.78 0.954 -2 0.953 72
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
19167356 2009 None None None None
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.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
19167356 Oocytes 34 27.0 1.5 2.0

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
19167356 Oocytes 67 26.0 2.5 2.0

F275S has 56 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
275 0 F275del,
274 5 I274V,
235 5 I235N,
272 5 G272D, G272S, G272V,
278 6 Y278H,
276 6 S276del,
271 6
279 6 F279I,
232 7
277 7 S277L, S277del, S277P, S277W,
236 7 L236Q, L236R,
273 7 L273F, L273V, L273R,
332 8
238 8 M238V, M238L, M238L,
239 9
269 10 G269D, G269S, G269del,
299 10
280 10 V280A, V280E,
234 10 Q234H, Q234H,
303 10 L303P,
233 11 L233P,
268 11 I268V, I268S,
270 11 F270S,
335 11 F335L, F335L, F335L,
328 11 I328del,
137 11 L137F, L137P,
282 11 L282P,
231 11 R231C, R231H, R231S,
267 11 Y267C,
229 12 G229D,
306 12 G306V, G306R, G306R,
336 12 A336S,
302 12 A302V, A302E, A302T,
237 12
281 12 Y281C,
248 13 W248C, W248C, W248R, W248R,
201 13 I201del,
240 13 H240R, H240P,
339 13 F339del, F339S,
310 13 V310I,
140 13 S140G, S140R, S140R, S140R,
230 13
205 13 V205M,
228 14
133 14 V133I,
283 14 A283G, A283T,
141 14 V141M,
134 14 L134P,
325 14 G325R, G325R, G325E, G325W,
300 14 A300T, A300S,
241 14 V241F, V241I, V241G,
309 14 T309I, T309R,
242 14 D242N, D242Y,
204 14 I204M, I204F,
136 14
130 15