KCNQ1 Variant K579E Detail

We estimate the penetrance of LQTS for KCNQ1 K579E is 37%. We are unaware of any observations of this variant in individuals. K579E is not present in gnomAD. K579E 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K579E around 37% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.3 0.872 0 0.806 47
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
VARIANT FEATURES ALONE: - 10 7 3 -
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.

K579E 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
579 0
578 4 E578K, E578V,
580 4 S580G, S580N,
577 5
581 5
576 7 V576I,
582 7
575 8
583 8 R583H, R583C, R583G,
574 8 I574V,
584 8 G584S,
573 9 F573L, F573L, F573L,
585 9 S585N,
572 10
586 10 N586D,
571 11 S571L, S571P,
587 11 T587M, T587R,
570 11 P570L,
588 11 I588F,
569 12 K569E,
589 12 G589D, G589S,
568 13 G568R, G568R, G568E,
590 13 A590T,
567 13 I567T, I567S,
591 13 R591H, R591C, R591L,
566 14 S566F, S566Y, S566P,
592 14
565 14
593 14 N593S,
564 15 D564H, D564N,
594 15 R594Q, R594P,