KCNQ1 Variant L273H Detail

We estimate the penetrance of LQTS for KCNQ1 L273H is 62%. We are unaware of any observations of this variant in individuals. L273H is not present in gnomAD. L273H 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 L273H around 62% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.8 1.0 -3 0.943 67
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.

L273H has 43 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
273 0 L273F, L273V, L273R,
274 4 I274V,
277 6 S277L, S277del, S277P, S277W,
269 6 G269D, G269S, G269del,
303 7 L303P,
271 7
275 7 F275del,
302 9 A302V, A302E, A302T,
299 10
268 10 I268V, I268S,
278 10 Y278H,
235 10 I235N,
267 11 Y267C,
238 11 M238V, M238L, M238L,
300 11 A300T, A300S,
333 12
330 12
334 12 V334A,
265 13 T265I,
137 13 L137F, L137P,
329 13 A329T,
301 13
331 13
336 13 A336S,
281 13 Y281C,
239 13
332 13
335 13 F335L, F335L, F335L,
307 14 V307L, V307L,
232 14
141 14 V141M,
236 14 L236Q, L236R,
296 14 F296S, F296L, F296L, F296L,
276 14 S276del,
134 14 L134P,
282 14 L282P,
318 14
298 15 S298I, S298N,
272 15 G272D, G272S, G272V,
328 15 I328del,
327 15 T327A, T327S, T327S,
338 15 S338F,
234 15 Q234H, Q234H,