KCNQ1 Variant F270L Detail

We estimate the penetrance of LQTS for KCNQ1 F270L is 38%. We are unaware of any observations of this variant in individuals. F270L is not present in gnomAD. F270L 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F270L around 38% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.83 0.798 1 0.897 42
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 7 3 -
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.

F270L has 35 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
267 7 Y267C,
238 10 M238V, M238L, M238L,
263 10
264 10
303 10 L303P,
334 11 V334A,
235 12 I235N,
335 12 F335L, F335L, F335L,
134 12 L134P,
336 12 A336S,
239 12
333 13
247 13 T247I,
337 13
338 13 S338F,
137 13 L137F, L137P,
130 13
248 13 W248C, W248C, W248R, W248R,
330 13
331 13
339 13 F339del, F339S,
269 14 G269D, G269S, G269del,
332 14
241 14 V241F, V241I, V241G,
302 14 A302V, A302E, A302T,
299 14
270 14 F270S,
242 14 D242N, D242Y,
310 14 V310I,
272 14 G272D, G272S, G272V,
304 14 W304R, W304R,
273 15 L273F, L273V, L273R,
300 15 A300T, A300S,
329 15 A329T,
133 15 V133I,