KCNQ1 Variant E596D Detail

We estimate the penetrance of LQTS for KCNQ1 E596D is 73%. We are unaware of any observations of this variant in individuals. E596D is not present in gnomAD. E596D 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E596D around 73% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.12 0.213 1 0.728 84
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.

E596D 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
596 0 E596del, E596K,
595 4 V595L, V595L,
597 4
594 5 R594Q, R594P,
598 5 K598R,
593 7 N593S,
599 7
592 8
600 8 T600M,
591 8 R591H, R591C, R591L,
601 8
590 9 A590T,
602 9
589 10 G589D, G589S,
603 10
588 11 I588F,
604 11
587 11 T587M, T587R,
605 11
586 12 N586D,
606 12
585 13 S585N,
607 13 A607T,
584 13 G584S,
608 13
583 14 R583H, R583C, R583G,
609 14
582 14
610 14
581 15
611 15 D611N, D611Y,