KCNQ1 Variant D428E Detail

We estimate the penetrance of LQTS for KCNQ1 D428E is 10%. We are unaware of any observations of this variant in individuals. D428E is not present in gnomAD. D428E has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT1 and 10 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D428E around 10% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.93 0.021 0 0.622 2
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.

D428E has 31 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
428 0 D428G,
427 4
429 4 N429S,
426 5
430 5
425 7 L425V,
431 7 V431L, V431L,
424 8 K424T,
432 8 T432I, T432A,
423 8
433 8 P433A,
422 9 K422T, K422R,
434 9 G434R, G434R,
421 10 K421N, K421N,
435 10
420 11 K420E, K420N, K420N,
436 11
419 11
437 11 M437V,
418 12 V418I,
438 12
417 13 V417M,
439 13
416 13 V416M,
440 13
415 14
441 14 P441S,
414 14
442 14 H442R,
413 15 K413R,
443 15