KCNQ1 Variant A383T Detail

We estimate the penetrance of LQTS for KCNQ1 A383T is 60%. We are unaware of any observations of this variant in individuals. A383T is not present in gnomAD. A383T 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A383T around 60% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.85 1.0 -1 0.851 63
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.

A383T has 33 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
383 0
384 4
382 5
386 5 N386K, N386K,
379 5 W379R, W379R, W379C, W379C, W379G,
391 6 T391A, T391I,
389 6 S389P,
385 6 E385K,
381 6 C381Y,
392 7 W392R, W392R, W392ins,
518 7 R518Q, R518G,
387 7 P387T,
380 8 R380S, R380S, R380G,
378 8 A378T,
390 8
515 9
388 9 D388H, D388N,
377 10
514 11 I514T,
511 11 R511Q, R511W,
519 12 R519H, R519C,
376 12
393 12 K393N,
522 12 Y522S,
512 13
375 13
521 13
516 13
517 13 I517T,
394 14 I394L,
513 14 T513A, T513S, T513S,
374 14 L374H, L374F,
510 14 H510R, H510Y,