KCNQ1 Variant K526Q Detail

We estimate the penetrance of LQTS for KCNQ1 K526Q is 13%. This variant was found in a total of 4 carriers in 0 papers or gnomAD, 0 had LQTS. K526Q is present in 4 alleles in gnomAD. K526Q has not been functionally characterized. This residue is located in a Mild_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 K526Q around 13% (1/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.66 0.943 0 0.879 16
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.

K526Q 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
526 0 K526Q, K526E,
525 5 A525T, A525V,
530 5
522 6 Y522S,
523 6
527 6
374 7 L374H, L374F,
529 7
524 7 V524G,
528 8
377 10
373 10 S373P,
370 10 A370V,
371 10 A371T,
531 10
378 10 A378T,
533 10 R533W, R533Q,
532 11
375 11
521 11
519 11 R519H, R519C,
534 12
520 12 M520R,
372 12
381 12 C381Y,
376 13
367 13 Q367H, Q367H,
369 14
380 14 R380S, R380S, R380G,
518 15 R518Q, R518G,