KCNQ1 Variant S468G Detail

We estimate the penetrance of LQTS for KCNQ1 S468G is 8%. This variant was found in a total of 2 carriers in 0 papers or gnomAD, 0 had LQTS. S468G is present in 2 alleles in gnomAD. S468G 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 0 individuals with LQT1 and 10 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S468G around 8% (0/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.22 0.001 1 0.639 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.

S468G 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
468 0 S468G, S468N,
467 4 K467R,
469 4
466 5
470 5
465 7
471 7
464 8 S464P,
472 8 L472P,
463 8 S463T,
473 8 E473Q,
462 9
474 9
461 10
475 10
460 11 G460S, G460D, G460C,
476 11 M476L, M476L, M476V,
459 11 D459N, D459V,
477 11 P477L, P477T,
458 12
478 12 H478Y,
457 13
479 13 F479L, F479L, F479L,
456 13 F456L, F456L, F456L,
480 13 M480T,
455 14 H455Y, H455Q, H455Q, H455R,
481 14
454 14
482 14 T482N, T482A, T482S, T482S,
453 15
483 15