KCNQ1 Variant E385Q Detail

We estimate the penetrance of LQTS for KCNQ1 E385Q is 25%. We are unaware of any observations of this variant in individuals. E385Q is not present in gnomAD. E385Q 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 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E385Q around 25% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.24 0.999 1 0.798 34
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.

E385Q has 28 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
385 0 E385K,
384 4
383 6
386 6 N386K, N386K,
382 7
515 7
387 7 P387T,
381 8 C381Y,
392 9 W392R, W392R, W392ins,
389 10 S389P,
518 10 R518Q, R518G,
388 11 D388H, D388N,
379 11 W379R, W379R, W379C, W379C, W379G,
511 11 R511Q, R511W,
391 11 T391A, T391I,
519 11 R519H, R519C,
512 11
378 11 A378T,
514 12 I514T,
380 12 R380S, R380S, R380G,
516 12
508 13 E508G,
390 13
377 13
522 14 Y522S,
513 14 T513A, T513S, T513S,
517 14 I517T,
510 14 H510R, H510Y,