KCNQ1 Variant F485L Detail

We estimate the penetrance of LQTS for KCNQ1 F485L is 10%. We are unaware of any observations of this variant in individuals. F485L is not present in gnomAD. F485L has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT1 and 10 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F485L around 10% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.42 0.002 -2 0.632 2
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.

F485L 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
485 0 F485S,
484 4
486 4 A486T,
483 5
487 5 E487K,
482 7 T482N, T482A, T482S, T482S,
488 7 D488E, D488E,
481 8
489 8
480 8 M480T,
490 8
479 9 F479L, F479L, F479L,
491 9
478 10 H478Y,
492 10 L492ins,
477 11 P477L, P477T,
493 11 G493A,
476 11 M476L, M476L, M476V,
494 11
475 12
495 12 T495S, T495S, T495A,
474 13
496 13
473 13 E473Q,
497 13 L497P,
472 14 L472P,
498 14
471 14
499 14 P499S,
470 15
500 15 I500L, I500V,