KCNH2 Variant L457H

Summary of observed carriers, functional annotations, and structural context for KCNH2 L457H. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

30%

3/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L457H has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 62% of WT with a standard error of 12%. 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 3 individuals with LQT2 and 7 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-6.011 0.092 -3 0.924 95

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 7 3 –

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 L457H.
Neighbour residue Distance (Å) Observed variants
457 0 L457P,
458 5
456 5 D456Y,
460 5 D460fsX,
454 6
453 6
461 6
459 6
455 7
507 9 P507S, P507L,
452 10
462 10 M462Ins,
528 11 R528X, R528P, R528W,
464 11 I464X,
463 11 F463L, F463L, F463L,
420 11 Y420C,
451 11 P451L,
450 12
505 12 A505V,
525 12 K525N, K525N,
417 12
449 12
508 13
421 13 T421M, T421fsX,
531 13 R531Del, R531Q, R531W,
509 13 D509N,
465 13
506 13 I506V,
504 13 A504V,
424 13
425 13
428 14 S428fsX, S428L, S428X,