KCNH2 Variant F424L Detail

We estimate the penetrance of LQTS for KCNH2 F424L is 56%. We are unaware of any observations of this variant in individuals. F424L is not present in gnomAD. F424L 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 F424L around 56% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.543 0.047 2 0.783 69
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 5 5 -
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.

F424L has 50 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
424 0
423 4
420 5 Y420C,
425 6
427 6 Y427S, Y427C, Y427H,
428 7 S428X, S428fsX, S428L,
421 7 T421fsX, T421M,
422 7 A422T,
426 7 P426H,
452 8
456 8 D456Y,
419 9
562 9 H562Q, H562R, H562Q, H562P,
455 9
429 10 A429V, A429P,
528 10 R528X, R528W, R528P,
453 10
418 11
459 11
417 11
431 11 F431L, F431L, F431L,
559 11 L559H, L559F,
611 11 Y611D,
563 11 W563G, W563C, W563C, W563X,
525 11 K525N, K525N,
566 11 C566G, C566F, C566R, C566S, C566S,
430 11
529 12
432 12
416 12
451 12 P451L,
531 12 R531W, R531Q, R531Del,
454 13
526 13
460 13 D460fsX,
558 13 A558E, A558P, A558V,
458 13
450 13
457 13 L457P,
565 13
607 14
561 14 A561V, A561P, A561T,
608 14
527 14
532 14
555 14
615 14 L615F, L615V,
415 14
522 15 G522E,
463 15 F463L, F463L, F463L,