KCNQ1 Variant I263L Detail

We estimate the penetrance of LQTS for KCNQ1 I263L is 43%. We are unaware of any observations of this variant in individuals. I263L is not present in gnomAD. I263L 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I263L around 43% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.94 0.894 1 0.813 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 6 4 -
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.

I263L 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 0
266 6 L266P,
259 6 R259C, R259H, R259L, R259G,
260 7
267 8 Y267C,
270 10 F270S,
246 11
242 12 D242N, D242Y,
251 12 L251P, L251Q,
271 13
250 13 L250H, L250P,
247 13 T247I,
355 13
241 13 V241F, V241I, V241G,
351 13 F351L, F351L, F351L, F351S,
265 14 T265I,
347 14 L347P, L347R,
339 14 F339del, F339S,
130 14
358 14 K358T,
342 14 L342F, L342P,
254 14 V254M, V254L, V254L,
338 14 S338F,
252 14 G252R,
264 15
255 15
238 15 M238V, M238L, M238L,