KCNQ1 Variant G589A Detail

We estimate the penetrance of LQTS for KCNQ1 G589A is 35%. We are unaware of any observations of this variant in individuals. G589A is not present in gnomAD. G589A has not been functionally characterized. This residue is located in a Mild_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 G589A around 35% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.69 0.969 -1 0.758 38
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.

G589A 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
589 0 G589D, G589S,
588 4 I588F,
590 4 A590T,
587 5 T587M, T587R,
591 5 R591H, R591C, R591L,
586 7 N586D,
592 7
585 8 S585N,
593 8 N593S,
584 8 G584S,
594 8 R594Q, R594P,
583 9 R583H, R583C, R583G,
595 9 V595L, V595L,
582 10
596 10 E596del, E596K,
581 11
597 11
580 11 S580G, S580N,
598 11 K598R,
579 12
599 12
578 13 E578K, E578V,
600 13 T600M,
577 13
601 13
576 14 V576I,
602 14
575 14
603 14
574 15 I574V,
604 15