KCNQ1 Variant S277L Detail

We estimate the penetrance of LQTS for KCNQ1 S277L is 74%. This variant was found in a total of 37 carriers in 15 papers or gnomAD, 27 had LQTS. S277L is not present in gnomAD. S277L has been functionally characterized in 2 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S277L around 74% (34/47).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.83 1.0 -2 0.974 85
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
34135346 2021 1 1 None None
32893267 2020 10 None 10 None
30758498 2019 10 None 3 None
29439887 2018 14 7 7 None
27041096 2016 1 None 1 None
26715165 2016 1 None 1 None
26496715 2016 1 None 1 None
24363352 2014 1 None None None
21895724 2011 3 2 1 None
21241800 2011 4 None 4 None
19716085 2009 2 None 2 None
19490272 2009 7 None 7 None
17470695 2007 3 None 3 None
14527360 2003 1 None 1 None
12808265 2003 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 37 10 27
VARIANT FEATURES ALONE: - 10 3 7 -
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)
21241800 Oocytes 0 -8.7 None None
21895724 CHO 0 0.0 None None

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)
21241800 Oocytes 18 -8.7 None None
21895724 CHO 10 0.0 1.0 None

S277L 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
277 0 S277L, S277del, S277P, S277W,
276 4 S276del,
302 5 A302V, A302E, A302T,
303 5 L303P,
280 5 V280A, V280E,
273 6 L273F, L273V, L273R,
274 6 I274V,
299 6
278 6 Y278H,
279 7 F279I,
275 7 F275del,
272 8 G272D, G272S, G272V,
281 8 Y281C,
300 9 A300T, A300S,
296 9 F296S, F296L, F296L, F296L,
282 9 L282P,
301 9
235 10 I235N,
283 10 A283G, A283T,
298 10 S298I, S298N,
284 10 E284K,
271 10
231 11 R231C, R231H, R231S,
270 11 F270S,
141 11 V141M,
232 11
318 11
269 11 G269D, G269S, G269del,
297 12 G297S, G297D, G297R,
137 12 L137F, L137P,
285 12
144 12 T144A,
140 13 S140G, S140R, S140R, S140R,
295 13
238 13 M238V, M238L, M238L,
330 13
234 13 Q234H, Q234H,
329 13 A329T,
236 14 L236Q, L236R,
228 14
229 14 G229D,
326 14
327 14 T327A, T327S, T327S,
333 14
307 15 V307L, V307L,
304 15 W304R, W304R,
138 15
315 15 Y315C, Y315S, Y315N, Y315H, Y315F,
268 15 I268V, I268S,
328 15 I328del,
313 15
308 15 V308F,
331 15
287 15 A287E, A287T, A287S,
145 15
325 15 G325R, G325R, G325E, G325W,