KCNH2 Variant F494L Detail

We estimate the penetrance of LQTS for KCNH2 F494L is 79%. We are unaware of any observations of this variant in individuals. F494L is not present in gnomAD. F494L has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F494L around 79% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.893 0.091 0 0.566 88
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 3 7 -
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.

F494L has 29 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
494 0 F494Del,
490 5 A490P, A490T,
493 6 Y493F, Y493H, Y493C, Y493Ins,
491 6 V491I,
498 6
495 7 K495X,
496 7
492 8 H492Y,
471 8 F471X,
499 9
489 9 I489F, I489I,
502 11 M502I, M502I, M502I,
487 11 G487S, G487R,
497 11 W497X, W497L,
467 11
470 11 N470D,
501 11 D501H, D501N, D501Y,
500 12 I500Del,
486 12
475 13 Y475Del, Y475C,
468 13 L468X, L468F, L468R,
488 13 R488H, R488C,
473 14 T473P,
472 14 R472X, R472C,
503 14
537 14 R537W,
466 15 D466E, D466E,
469 15
505 15 A505V,