KCNQ1 Variant H614del Detail

We estimate the penetrance of LQTS for KCNQ1 H614del is 61%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 1 had LQTS. H614del is not present in gnomAD. H614del has not been functionally characterized. This residue is located in a NA region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 H614del around 61% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
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.

H614del 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
614 0 H614del,
613 4
615 4
612 5
616 5
611 7 D611N, D611Y,
617 7
610 8
618 8
609 8
619 8 L619M,
608 9
620 9
607 10 A607T,
621 10 G621S, G621C, G621D,
606 11
622 11 G622S,
605 11
623 11
604 12
624 12
603 13
625 13 P625R,
602 13
626 13 G626S,
601 14
627 14
600 14 T600M,
628 14 G628S, G628D,
599 15
629 15 G629S,