KCNQ1 Variant E473A Detail

We estimate the penetrance of LQTS for KCNQ1 E473A is 15%. We are unaware of any observations of this variant in individuals. E473A is not present in gnomAD. E473A 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 E473A around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.85 0.232 -2 0.744 8
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.

E473A 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
473 0 E473Q,
472 4 L472P,
474 4
471 5
475 5
470 7
476 7 M476L, M476L, M476V,
469 8
477 8 P477L, P477T,
468 8 S468G, S468N,
478 8 H478Y,
467 9 K467R,
479 9 F479L, F479L, F479L,
466 10
480 10 M480T,
465 11
481 11
464 11 S464P,
482 11 T482N, T482A, T482S, T482S,
463 12 S463T,
483 12
462 13
484 13
461 13
485 13 F485S,
460 14 G460S, G460D, G460C,
486 14 A486T,
459 14 D459N, D459V,
487 14 E487K,
458 15
488 15 D488E, D488E,