KCNQ1 Variant S464P Detail

We estimate the penetrance of LQTS for KCNQ1 S464P is 9%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. S464P is present in 1 alleles in gnomAD. S464P 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 S464P around 9% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.0 0.0 4 0.574 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.

S464P 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
464 0 S464P,
463 4 S463T,
465 4
462 5
466 5
461 7
467 7 K467R,
460 8 G460S, G460D, G460C,
468 8 S468G, S468N,
459 8 D459N, D459V,
469 8
458 9
470 9
457 10
471 10
456 11 F456L, F456L, F456L,
472 11 L472P,
455 11 H455Y, H455Q, H455Q, H455R,
473 11 E473Q,
454 12
474 12
453 13
475 13
452 13 R452Q, R452W, R452L,
476 13 M476L, M476L, M476V,
451 14 R451Q, R451W,
477 14 P477L, P477T,
450 14 E450K,
478 14 H478Y,
449 15 E449K,
479 15 F479L, F479L, F479L,