KCNH2 Variant F406L Detail

We estimate the penetrance of LQTS for KCNH2 F406L is 19%. We are unaware of any observations of this variant in individuals. F406L is not present in gnomAD. F406L has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F406L around 19% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.702 0.025 0 0.871 26
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 LQT2 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.

F406L has 28 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 since the functional KV11.1 channel (protein product of KCNH2/hERG) 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
406 0
407 5
405 6
404 6
410 6 W410X,
409 7 V409L, V409L, V409M,
408 7
400 8 I400N,
401 9
469 9
411 9
473 10 T473P,
413 10 L413P,
403 11
402 11 H402R,
466 11 D466E, D466E,
399 12
414 12 I414fsX,
465 12
541 12 R541H, R541C,
412 12 W412X,
470 12 N470D,
474 12 T474I,
462 12 M462Ins,
472 13 R472C, R472X,
398 13 W398L, W398X,
468 13 L468X, L468R, L468F,
538 14