KCNQ1 Variant K420E Detail

We estimate the penetrance of LQTS for KCNQ1 K420E is 30%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. K420E is present in 1 alleles in gnomAD. K420E 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K420E around 30% (3/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.88 0.077 0 0.664 39
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: - 1 1 0
VARIANT FEATURES ALONE: - 10 7 3 -
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.

K420E 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
420 0 K420E, K420N, K420N,
419 4
421 4 K421N, K421N,
418 5 V418I,
422 5 K422T, K422R,
417 7 V417M,
423 7
416 8 V416M,
424 8 K424T,
415 8
425 8 L425V,
414 9
426 9
413 10 K413R,
427 10
412 11 P412S,
428 11 D428G,
411 11
429 11 N429S,
410 12
430 12
409 13
431 13 V431L, V431L,
408 13 P408A,
432 13 T432I, T432A,
407 14
433 14 P433A,
406 14
434 14 G434R, G434R,
405 15
435 15