KCNQ1 Variant T391A Detail

We estimate the penetrance of LQTS for KCNQ1 T391A is 61%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. T391A is present in 1 alleles in gnomAD. T391A has not been functionally characterized. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T391A around 61% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.51 1.0 0 0.878 69
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.

T391A has 30 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
391 0 T391A, T391I,
390 4
389 5 S389P,
392 5 W392R, W392R, W392ins,
383 6
393 7 K393N,
379 7 W379R, W379R, W379C, W379C, W379G,
380 7 R380S, R380S, R380G,
384 7
386 8 N386K, N386K,
518 8 R518Q, R518G,
387 8 P387T,
394 9 I394L,
388 9 D388H, D388N,
381 10 C381Y,
382 10
514 10 I514T,
385 11 E385K,
511 11 R511Q, R511W,
378 11 A378T,
377 11
376 12
515 12
521 13
510 13 H510R, H510Y,
517 13 I517T,
512 14
375 14
513 14 T513A, T513S, T513S,
516 15