KCNH2 Variant F424V

Summary of observed carriers, functional annotations, and structural context for KCNH2 F424V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

23%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

F424V has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 128% of WT with a standard error of 10%. 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 (%)
-5.728 0.057 0 0.809 69

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
Literature, cohort, and gnomAD – 0 0 0 –
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 F424V.
Neighbour residue Distance (Å) Observed variants
424 0
423 4
420 5 Y420C,
425 6
427 6 Y427H, Y427S, Y427C,
428 7 S428fsX, S428X, S428L,
421 7 T421fsX, T421M,
422 7 A422T,
426 7 P426H,
452 8
456 8 D456Y,
419 9
562 9 H562P, H562R, H562Q, H562Q,
455 9
429 10 A429P, A429V,
528 10 R528W, R528X, R528P,
453 10
418 11
459 11
417 11
431 11 F431L, F431L, F431L,
559 11 L559F, L559H,
611 11 Y611D,
563 11 W563G, W563C, W563C, W563X,
525 11 K525N, K525N,
566 11 C566S, C566R, C566G, C566S, C566F,
430 11
529 12
432 12
416 12
451 12 P451L,
531 12 R531W, R531Del, R531Q,
454 13
526 13
460 13 D460fsX,
558 13 A558P, A558E, A558V,
458 13
450 13
457 13 L457P,
565 13
607 14
561 14 A561T, A561P, A561V,
608 14
527 14
532 14
555 14
615 14 L615V, L615F
415 14
522 15 G522E,
463 15 F463L, F463L, F463L,