KCNH2 Variant V455L

Summary of observed carriers, functional annotations, and structural context for KCNH2 V455L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

11%

90% CI: 0.8% – 30.3%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

V455L has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 94% of WT with a standard error of 13%. 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 (%)
-2.528 0.193 1 0.725 84

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 V455L.
Neighbour residue Distance (Å) Observed variants
455 0
454 4
456 5 D456Y,
458 5
453 6
452 6
457 7 L457P,
459 7
451 7 P451L,
420 7 Y420C,
460 9 D460fsX,
424 9
450 10
417 10
461 10
462 11 M462Ins,
449 11
421 11 T421fsX, T421M,
416 12
528 12 R528W, R528X, R528P,
425 13
463 13 F463L, F463L, F463L,
423 13
428 13 S428fsX, S428X, S428L,
418 13
419 14
413 14 L413P,
531 14 R531W, R531Del, R531Q
525 14 K525N, K525N,
427 14 Y427H, Y427S, Y427C,
422 14 A422T,
414 15 I414fsX,
464 15 I464X,