KCNQ1 Variant I394L Detail

We estimate the penetrance of LQTS for KCNQ1 I394L is 17%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. I394L is present in 1 alleles in gnomAD. I394L has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I394L around 17% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.23 0.031 0 0.595 21
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
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.

I394L has 18 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
394 0 I394L,
393 5 K393N,
391 9 T391A, T391I,
392 9 W392R, W392R, W392ins,
514 10 I514T,
390 11
518 11 R518Q, R518G,
380 11 R380S, R380S, R380G,
510 12 H510R, H510Y,
389 12 S389P,
511 12 R511Q, R511W,
517 13 I517T,
513 13 T513A, T513S, T513S,
383 14
521 14
384 14
387 14 P387T,
379 15 W379R, W379R, W379C, W379C, W379G,