KCNQ1 Variant R583S Detail

We estimate the penetrance of LQTS for KCNQ1 R583S is 48%. We are unaware of any observations of this variant in individuals. R583S is not present in gnomAD. R583S 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R583S around 48% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.65 0.638 -1 0.806 56
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 6 4 -
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.

R583S 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
583 0 R583H, R583C, R583G,
582 4
584 4 G584S,
581 5
585 5 S585N,
580 7 S580G, S580N,
586 7 N586D,
579 8
587 8 T587M, T587R,
578 8 E578K, E578V,
588 8 I588F,
577 9
589 9 G589D, G589S,
576 10 V576I,
590 10 A590T,
575 11
591 11 R591H, R591C, R591L,
574 11 I574V,
592 11
573 12 F573L, F573L, F573L,
593 12 N593S,
572 13
594 13 R594Q, R594P,
571 13 S571L, S571P,
595 13 V595L, V595L,
570 14 P570L,
596 14 E596del, E596K,
569 14 K569E,
597 14
568 15 G568R, G568R, G568E,
598 15 K598R,