KCNQ1 Variant F423I Detail

We estimate the penetrance of LQTS for KCNQ1 F423I is 15%. We are unaware of any observations of this variant in individuals. F423I is not present in gnomAD. F423I 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 F423I around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.54 0.001 0 0.572 13
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.

F423I 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
423 0
422 4 K422T, K422R,
424 4 K424T,
421 5 K421N, K421N,
425 5 L425V,
420 7 K420E, K420N, K420N,
426 7
419 8
427 8
418 8 V418I,
428 8 D428G,
417 9 V417M,
429 9 N429S,
416 10 V416M,
430 10
415 11
431 11 V431L, V431L,
414 11
432 11 T432I, T432A,
413 12 K413R,
433 12 P433A,
412 13 P412S,
434 13 G434R, G434R,
411 13
435 13
410 14
436 14
409 14
437 14 M437V,
408 15 P408A,
438 15