KCNQ1 Variant T432I Detail

We estimate the penetrance of LQTS for KCNQ1 T432I is 8%. This variant was found in a total of 3 carriers in 0 papers or gnomAD, 0 had LQTS. T432I is present in 3 alleles in gnomAD. T432I 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 T432I around 8% (1/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.95 0.002 -2 0.533 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
LITERATURE, COHORT, AND GNOMAD: - 3 3 0
VARIANT FEATURES ALONE: - 10 9 1 -
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.

T432I 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
432 0 T432I, T432A,
431 4 V431L, V431L,
433 4 P433A,
430 5
434 5 G434R, G434R,
429 7 N429S,
435 7
428 8 D428G,
436 8
427 8
437 8 M437V,
426 9
438 9
425 10 L425V,
439 10
424 11 K424T,
440 11
423 11
441 11 P441S,
422 12 K422T, K422R,
442 12 H442R,
421 13 K421N, K421N,
443 13
420 13 K420E, K420N, K420N,
444 13 T444M, T444K,
419 14
445 14
418 14 V418I,
446 14 D446E, D446E, D446E, D446E, D446N,
417 15 V417M,
447 15 P447H,