KCNH2 Variant F498L Detail

We estimate the penetrance of LQTS for KCNH2 F498L is 62%. We are unaware of any observations of this variant in individuals. F498L is not present in gnomAD. F498L 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F498L around 62% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.56 0.783 0 0.93 70
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 4 6 -
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.

F498L has 37 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
498 0
493 5 Y493Ins, Y493H, Y493F, Y493C,
502 5 M502I, M502I, M502I,
499 5
501 6 D501H, D501Y, D501N,
494 6 F494Del,
496 7
500 7 I500Del,
467 7
497 8 W497L, W497X,
471 9 F471X,
503 9
470 9 N470D,
495 9 K495X,
490 9 A490T, A490P,
505 10 A505V,
504 10 A504V,
534 10 R534C,
492 10 H492Y,
466 10 D466E, D466E,
468 11 L468X, L468R, L468F,
491 11 V491I,
537 11 R537W,
506 11 I506V,
464 11 I464X,
530 12
489 12 I489I, I489F,
533 12
463 12 F463L, F463L, F463L,
469 12
531 13 R531W, R531Del, R531Q,
465 13
473 13 T473P,
527 14
538 14
475 14 Y475C, Y475Del,
472 15 R472X, R472C,