KCNQ1 Variant F479Y Detail

We estimate the penetrance of LQTS for KCNQ1 F479Y is 45%. We are unaware of any observations of this variant in individuals. F479Y is not present in gnomAD. F479Y 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F479Y around 45% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.57 0.026 1 0.656 54
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.

F479Y 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
479 0 F479L, F479L, F479L,
478 4 H478Y,
480 4 M480T,
477 5 P477L, P477T,
481 5
476 7 M476L, M476L, M476V,
482 7 T482N, T482A, T482S, T482S,
475 8
483 8
474 8
484 8
473 9 E473Q,
485 9 F485S,
472 10 L472P,
486 10 A486T,
471 11
487 11 E487K,
470 11
488 11 D488E, D488E,
469 12
489 12
468 13 S468G, S468N,
490 13
467 13 K467R,
491 13
466 14
492 14 L492ins,
465 14
493 14 G493A,
464 15 S464P,
494 15