KCNQ1 Variant L271M Detail

We estimate the penetrance of LQTS for KCNQ1 L271M is 53%. We are unaware of any observations of this variant in individuals. L271M is not present in gnomAD. L271M 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 L271M around 53% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.94 0.995 2 0.8 55
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.

L271M has 54 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
271 0
272 5 G272D, G272S, G272V,
269 5 G269D, G269S, G269del,
268 5 I268V, I268S,
267 5 Y267C,
274 5 I274V,
275 6 F275del,
238 6 M238V, M238L, M238L,
270 6 F270S,
239 7
273 7 L273F, L273V, L273R,
235 8 I235N,
248 9 W248C, W248C, W248R, W248R,
236 9 L236Q, L236R,
276 10 S276del,
242 10 D242N, D242Y,
265 10 T265I,
247 10 T247I,
277 10 S277L, S277del, S277P, S277W,
241 10 V241F, V241I, V241G,
264 11
130 11
278 11 Y278H,
137 11 L137F, L137P,
240 11 H240R, H240P,
232 12
134 12 L134P,
303 12 L303P,
310 12 V310I,
279 12 F279I,
251 12 L251P, L251Q,
133 12 V133I,
306 12 G306V, G306R, G306R,
263 13
237 13
234 13 Q234H, Q234H,
245 13 G245V,
299 13
201 13 I201del,
335 13 F335L, F335L, F335L,
246 13
336 14 A336S,
233 14 L233P,
198 14 I198V, I198T,
339 14 F339del, F339S,
332 14
243 14 R243H, R243C, R243P, R243S,
302 15 A302V, A302E, A302T,
250 15 L250H, L250P,
342 15 L342F, L342P,
309 15 T309I, T309R,
334 15 V334A,
280 15 V280A, V280E,
252 15 G252R,