KCNH2 Variant F463L

Summary of observed carriers, functional annotations, and structural context for KCNH2 F463L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

36%

9/18 effective observations

Total carriers

8

7 LQT2 · 1 unaffected

Functional studies

3

Publications with functional data

F463L 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 (%)
-5.56 0.975 0 0.974 79

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
19065538 2008 1 0 1
France Cohort 2020 5 0 5
19215240 2009 3 1 2
Literature, cohort, and gnomAD – 8 1 7 –
Variant features alone – 10 8 2 –

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

Functional data

Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.

Homomeric channel data

Published electrophysiology measurements (homomeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
19215240 HEK293 0 None None None None
23980197 Xeno 6.4 None None None
29573040 HEK293 None None None None

Heteromeric channel data

Published electrophysiology measurements (heteromeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
19215240 HEK293 37 50 12.6 None None
23980197 Xeno None None None
29573040 HEK293 29 7.44 -45.32 None

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 F463L.
Neighbour residue Distance (Å) Observed variants
463 0 F463L, F463L, F463L,
531 5 R531W, R531Del, R531Q,
462 6 M462Ins,
466 6 D466E, D466E,
459 6
464 6 I464X,
460 6 D460fsX,
504 7 A504V,
534 7 R534C,
417 7
505 7 A505V,
465 7
414 7 I414fsX,
461 7
467 8
501 8 D501N, D501H, D501Y,
418 8
528 9 R528W, R528X, R528P,
421 9 T421fsX, T421M,
410 10 W410X,
502 10 M502I, M502I, M502I,
458 10
413 10 L413P,
530 10
503 10
456 11 D456Y,
469 11
468 11 L468F, L468X, L468R,
506 11 I506V,
420 11 Y420C,
470 11 N470D,
532 11
457 11 L457P,
533 11
527 11
507 11 P507S, P507L,
415 11
411 12
416 12
529 12
500 12 I500Del,
535 12 V535M,
498 12
419 12
538 12
537 13 R537W
422 13 A422T,
455 13
425 13
407 13
493 14 Y493H, Y493C, Y493F, Y493Ins,
525 14 K525N, K525N,
471 14 F471X,
497 14 W497L, W497X,
526 14
499 14
424 15
536 15 A536X,
508 15