KCNQ1 Variant L266M Detail

We estimate the penetrance of LQTS for KCNQ1 L266M is 55%. We are unaware of any observations of this variant in individuals. L266M is not present in gnomAD. L266M 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 L266M around 55% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.79 0.978 1 0.743 63
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.

L266M has 27 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
263 6
339 11 F339del, F339S,
259 11 R259C, R259H, R259L, R259G,
260 12
334 12 V334A,
335 12 F335L, F335L, F335L,
336 12 A336S,
274 12 I274V,
251 12 L251P, L251Q,
266 13 L266P,
265 13 T265I,
269 13 G269D, G269S, G269del,
347 13 L347P, L347R,
238 13 M238V, M238L, M238L,
242 14 D242N, D242Y,
268 14 I268V, I268S,
246 14
333 14
351 14 F351L, F351L, F351L, F351S,
241 14 V241F, V241I, V241G,
338 14 S338F,
247 14 T247I,
239 15
255 15
250 15 L250H, L250P,
130 15
310 15 V310I,