KCNH2 Variant F494V

Summary of observed carriers, functional annotations, and structural context for KCNH2 F494V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

28%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

F494V has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 117% of WT with a standard error of 6%. 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 (%)
-5.803 0.786 -1 0.904 88

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 F494V.
Neighbour residue Distance (Å) Observed variants
494 0 F494Del,
490 5 A490T, A490P,
493 6 Y493C, Y493H, Y493Ins, Y493F,
491 6 V491I,
498 6
495 7 K495X,
496 7
492 8 H492Y,
471 8 F471X,
499 9
489 9 I489I, I489F,
502 11 M502I, M502I, M502I,
487 11 G487S, G487R,
497 11 W497L, W497X,
467 11
470 11 N470D,
501 11 D501N, D501Y, D501H,
500 12 I500Del,
486 12
475 13 Y475Del, Y475C,
468 13 L468X, L468F, L468R,
488 13 R488C, R488H,
473 14 T473P,
472 14 R472X, R472C,
503 14
537 14 R537W,
466 15 D466E, D466E,
469 15
505 15 A505V,