KCNH2 Variant V454L

Summary of observed carriers, functional annotations, and structural context for KCNH2 V454L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

17%

90% CI: 2.6% – 38.4%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

V454L has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 133% of WT with a standard error of 22%. 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 1 individuals with LQT2 and 9 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-2.492 0.597 1 0.761 76

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 9 1 –

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 V454L.
Neighbour residue Distance (Å) Observed variants
454 0
453 4
455 4
457 6 L457P,
451 6 P451L,
458 7
456 7 D456Y,
452 7
450 7
449 8
459 10
460 10 D460fsX,
461 11
420 11 Y420C,
424 13
462 13 M462Ins,
417 14
528 14 R528W, R528X, R528P
428 14 S428fsX, S428X, S428L,
421 15 T421fsX, T421M,
507 15 P507S, P507L,
525 15 K525N, K525N,
425 15