KCNH2 Variant F431L Detail

We estimate the penetrance of LQTS for KCNH2 F431L is 78%. This variant was found in a total of 2 carriers in 1 papers or gnomAD, 2 had LQTS. F431L is not present in gnomAD. F431L 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 F431L around 78% (9/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.71 0.947 0 0.965 82
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
Japan Cohort 2020 2 0 2
LITERATURE, COHORT, AND GNOMAD: - 2 0 2 -
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.

F431L has 48 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
431 0 F431L, F431L, F431L,
430 4
427 5 Y427S, Y427C, Y427H,
569 5 Y569H, Y569C, Y569X,
432 6
429 7 A429V, A429P,
607 7
566 7 C566S, C566S, C566F, C566R, C566G,
428 7 S428fsX, S428X, S428L,
610 7
611 7 Y611D,
426 8 P426H,
570 9
565 9
573 9
562 10 H562P, H562Q, H562Q, H562R,
614 10 A614T, A614V,
609 10 D609G, D609N,
567 10 I567M, I567T,
606 10 S606Del, S606P, S606F,
608 11
425 11
424 11
612 11 V612L, V612L, V612A,
572 11 G572D, G572S, G572C, G572R,
423 12
568 12 W568C, W568C,
613 12 T613A, T613M, T613L, T613K,
605 12 P605L,
615 12 L615F, L615V,
574 12 M574L, M574V, M574L,
586 12 L586M,
571 12 I571L, I571V,
522 13 G522E,
585 13 W585C, W585C,
563 13 W563C, W563X, W563C, W563G,
564 13 L564L,
523 13
525 13 K525N, K525N,
452 14
561 14 A561P, A561T, A561V,
422 14 A422T,
604 14 G604D, G604C, G604S,
526 14
520 15
618 15 T618S, T618S,
589 15 L589P,
576 15