KCNH2 Variant F431L

Summary of observed carriers, functional annotations, and structural context for KCNH2 F431L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

28%

4/12 effective observations

Total carriers

2

2 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

F431L has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 0%. In our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong.

Variant features alone are equivalent to phenotyping 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-5.71 0.947 0 0.965 82

PROVEAN scores below -2 suggest deleterious impact. REVEL scores above 0.5–0.75 are often interpreted as likely pathogenic. PolyPhen-2 scores above 0.85 are typically pathogenic. BLAST-PSSM reflects evolutionary conservation; more negative values indicate rarer substitutions. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).

Reported carrier data

Observed carriers by publication or cohort.
Source Year Carriers Unaffected LQT2 Other Disease
Japan Cohort 2020 2 0 2
Literature, cohort, and gnomAD – 2 0 2 –
Variant features alone – 10 8 2 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD. Note that 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 15Å window.

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