KCNQ1 Variant W392ins Detail

We estimate the penetrance of LQTS for KCNQ1 W392ins is 61%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 1 had LQTS. W392ins is not present in gnomAD. W392ins has not been functionally characterized. This residue is located in a NA 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 W392ins around 61% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
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.

W392ins 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
392 0 W392R, W392R, W392ins,
391 5 T391A, T391I,
387 6 P387T,
389 6 S389P,
511 6 R511Q, R511W,
384 6
383 7
514 7 I514T,
518 7 R518Q, R518G,
386 7 N386K, N386K,
393 8 K393N,
390 8
388 8 D388H, D388N,
510 9 H510R, H510Y,
515 9
394 9 I394L,
385 9 E385K,
380 10 R380S, R380S, R380G,
512 10
381 10 C381Y,
508 10 E508G,
513 11 T513A, T513S, T513S,
379 11 W379R, W379R, W379C, W379C, W379G,
382 11
517 12 I517T,
516 12
377 13
378 14 A378T,
509 14 H509Q, H509Q, H509R,
521 14
519 14 R519H, R519C,