KCNQ1 Variant E578A Detail

We estimate the penetrance of LQTS for KCNQ1 E578A is 69%. We are unaware of any observations of this variant in individuals. E578A is not present in gnomAD. E578A has not been functionally characterized. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E578A around 69% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.93 0.1 -1 0.731 80
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.

E578A 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
578 0 E578K, E578V,
577 4
579 4
576 5 V576I,
580 5 S580G, S580N,
575 7
581 7
574 8 I574V,
582 8
573 8 F573L, F573L, F573L,
583 8 R583H, R583C, R583G,
572 9
584 9 G584S,
571 10 S571L, S571P,
585 10 S585N,
570 11 P570L,
586 11 N586D,
569 11 K569E,
587 11 T587M, T587R,
568 12 G568R, G568R, G568E,
588 12 I588F,
567 13 I567T, I567S,
589 13 G589D, G589S,
566 13 S566F, S566Y, S566P,
590 13 A590T,
565 14
591 14 R591H, R591C, R591L,
564 14 D564H, D564N,
592 14
563 15
593 15 N593S,