KCNQ1 Variant E449A Detail

We estimate the penetrance of LQTS for KCNQ1 E449A is 11%. We are unaware of any observations of this variant in individuals. E449A is not present in gnomAD. E449A 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E449A around 11% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.18 0.488 0 0.599 6
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.

E449A 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
449 0 E449K,
448 4 P448R, P448Q, P448L, P448S,
450 4 E450K,
447 5 P447H,
451 5 R451Q, R451W,
446 7 D446E, D446E, D446E, D446E, D446N,
452 7 R452Q, R452W, R452L,
445 8
453 8
444 8 T444M, T444K,
454 8
443 9
455 9 H455Y, H455Q, H455Q, H455R,
442 10 H442R,
456 10 F456L, F456L, F456L,
441 11 P441S,
457 11
440 11
458 11
439 12
459 12 D459N, D459V,
438 13
460 13 G460S, G460D, G460C,
437 13 M437V,
461 13
436 14
462 14
435 14
463 14 S463T,
434 15 G434R, G434R,
464 15 S464P,