KCNQ1 Variant S585N Detail

We estimate the penetrance of LQTS for KCNQ1 S585N is 28%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. S585N is present in 1 alleles in gnomAD. S585N 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 S585N around 28% (3/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.21 0.002 0 0.509 34
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.

S585N 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
585 0 S585N,
584 4 G584S,
586 4 N586D,
583 5 R583H, R583C, R583G,
587 5 T587M, T587R,
582 7
588 7 I588F,
581 8
589 8 G589D, G589S,
580 8 S580G, S580N,
590 8 A590T,
579 9
591 9 R591H, R591C, R591L,
578 10 E578K, E578V,
592 10
577 11
593 11 N593S,
576 11 V576I,
594 11 R594Q, R594P,
575 12
595 12 V595L, V595L,
574 13 I574V,
596 13 E596del, E596K,
573 13 F573L, F573L, F573L,
597 13
572 14
598 14 K598R,
571 14 S571L, S571P,
599 14
570 15 P570L,
600 15 T600M,