KCNQ1 Variant P433A Detail

We estimate the penetrance of LQTS for KCNQ1 P433A is 10%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. P433A is present in 1 alleles in gnomAD. P433A 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 P433A around 10% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.34 0.021 0 0.51 2
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.

P433A 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
433 0 P433A,
432 4 T432I, T432A,
434 4 G434R, G434R,
431 5 V431L, V431L,
435 5
430 7
436 7
429 8 N429S,
437 8 M437V,
428 8 D428G,
438 8
427 9
439 9
426 10
440 10
425 11 L425V,
441 11 P441S,
424 11 K424T,
442 11 H442R,
423 12
443 12
422 13 K422T, K422R,
444 13 T444M, T444K,
421 13 K421N, K421N,
445 13
420 14 K420E, K420N, K420N,
446 14 D446E, D446E, D446E, D446E, D446N,
419 14
447 14 P447H,
418 15 V418I,
448 15 P448R, P448Q, P448L, P448S,