KCNQ1 Variant F523L Detail

We estimate the penetrance of LQTS for KCNQ1 F523L is 39%. We are unaware of any observations of this variant in individuals. F523L is not present in gnomAD. F523L 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F523L around 39% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.19 0.104 3 0.702 48
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: - 0 0 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.

F523L 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
523 0
522 5 Y522S,
519 6 R519H, R519C,
524 6 V524G,
526 6 K526Q, K526E,
520 6 M520R,
525 7 A525T, A525V,
521 8
527 9
377 9
381 9 C381Y,
516 9
374 9 L374H, L374F,
517 10 I517T,
378 10 A378T,
528 10
518 11 R518Q, R518G,
530 11
515 11
373 11 S373P,
380 12 R380S, R380S, R380G,
529 12
375 13
376 13
370 13 A370V,
514 14 I514T,
371 14 A371T,
384 14
372 14
531 15
513 15 T513A, T513S, T513S,