KCNH2 Variant L499F Detail

We estimate the penetrance of LQTS for KCNH2 L499F is 52%. We are unaware of any observations of this variant in individuals. L499F is not present in gnomAD. L499F 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L499F around 52% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.99 0.027 0 0.777 60
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.

L499F 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 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
499 0
500 4 I500Del,
498 5
502 6 M502I, M502I, M502I,
496 6
501 7 D501H, D501N, D501Y,
503 7
497 8 W497X, W497L,
495 8 K495X,
494 9 F494Del,
493 9 Y493F, Y493C, Y493Ins, Y493H,
530 10
504 10 A504V,
505 11 A505V,
533 11
506 11 I506V,
467 12
534 12 R534C,
537 12 R537W,
527 12
492 13 H492Y,
531 13 R531W, R531Q, R531Del,
490 13 A490P, A490T,
470 13 N470D,
471 14 F471X,
491 14 V491I,
466 14 D466E, D466E,
463 14 F463L, F463L, F463L,
464 15 I464X,
529 15
532 15