KCNQ1 Variant S463T Detail

We estimate the penetrance of LQTS for KCNQ1 S463T is 6%. This variant was found in a total of 12 carriers in 0 papers or gnomAD, 0 had LQTS. S463T is present in 12 alleles in gnomAD. S463T has not been functionally characterized. This residue is located in a Non_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 S463T around 6% (1/22).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.39 0.034 1 0.493 1
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.

S463T 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
463 0 S463T,
462 4
464 4 S464P,
461 5
465 5
460 7 G460S, G460D, G460C,
466 7
459 8 D459N, D459V,
467 8 K467R,
458 8
468 8 S468G, S468N,
457 9
469 9
456 10 F456L, F456L, F456L,
470 10
455 11 H455Y, H455Q, H455Q, H455R,
471 11
454 11
472 11 L472P,
453 12
473 12 E473Q,
452 13 R452Q, R452W, R452L,
474 13
451 13 R451Q, R451W,
475 13
450 14 E450K,
476 14 M476L, M476L, M476V,
449 14 E449K,
477 14 P477L, P477T,
448 15 P448R, P448Q, P448L, P448S,
478 15 H478Y,