KCNH2 Variant A453D

Summary of observed carriers, functional annotations, and structural context for KCNH2 A453D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

20%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

A453D 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 10%. 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 (%)
0.374 0.001 0 0.52 74

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 A453D.
Neighbour residue Distance (Å) Observed variants
453 0
454 4
452 4
456 5 D456Y,
450 6
455 6
451 6 P451L,
457 6 L457P,
449 8
458 9
459 10
460 10 D460fsX,
420 10 Y420C,
424 10
428 11 S428fsX, S428X, S428L,
525 12 K525N, K525N,
528 12 R528W, R528X, R528P
425 12
461 13
427 13 Y427H, Y427S, Y427C,
432 13
421 13 T421fsX, T421M,
507 14 P507S, P507L,
509 14 D509N,
429 14 A429P, A429V,
417 15
423 15
426 15 P426H,
522 15 G522E,
462 15 M462Ins,