KCNQ1 Variant S580N Detail

We estimate the penetrance of LQTS for KCNQ1 S580N is 17%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. S580N is present in 1 alleles in gnomAD. S580N 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S580N around 17% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.38 0.001 0 0.504 18
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.

S580N 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
580 0 S580G, S580N,
579 4
581 4
578 5 E578K, E578V,
582 5
577 7
583 7 R583H, R583C, R583G,
576 8 V576I,
584 8 G584S,
575 8
585 8 S585N,
574 9 I574V,
586 9 N586D,
573 10 F573L, F573L, F573L,
587 10 T587M, T587R,
572 11
588 11 I588F,
571 11 S571L, S571P,
589 11 G589D, G589S,
570 12 P570L,
590 12 A590T,
569 13 K569E,
591 13 R591H, R591C, R591L,
568 13 G568R, G568R, G568E,
592 13
567 14 I567T, I567S,
593 14 N593S,
566 14 S566F, S566Y, S566P,
594 14 R594Q, R594P,
565 15
595 15 V595L, V595L,