KCNQ1 Variant A590S Detail

We estimate the penetrance of LQTS for KCNQ1 A590S is 38%. We are unaware of any observations of this variant in individuals. A590S is not present in gnomAD. A590S 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 A590S around 38% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.29 0.013 1 0.641 46
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.

A590S 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
590 0 A590T,
589 4 G589D, G589S,
591 4 R591H, R591C, R591L,
588 5 I588F,
592 5
587 7 T587M, T587R,
593 7 N593S,
586 8 N586D,
594 8 R594Q, R594P,
585 8 S585N,
595 8 V595L, V595L,
584 9 G584S,
596 9 E596del, E596K,
583 10 R583H, R583C, R583G,
597 10
582 11
598 11 K598R,
581 11
599 11
580 12 S580G, S580N,
600 12 T600M,
579 13
601 13
578 13 E578K, E578V,
602 13
577 14
603 14
576 14 V576I,
604 14
575 15
605 15