KCNH2 Variant D456N

Summary of observed carriers, functional annotations, and structural context for KCNH2 D456N. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

18%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

D456N has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 109% of WT with a standard error of 17%. 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 (%)
-4.383 0.975 1 0.914 90

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 D456N.
Neighbour residue Distance (Å) Observed variants
456 0 D456Y,
457 5 L457P,
455 5
453 5
459 5
460 6 D460fsX,
458 7
420 7 Y420C,
454 7
452 7
528 8 R528P, R528X, R528W,
424 8
421 9 T421M, T421fsX,
425 9
525 9 K525N, K525N,
461 9
428 10 S428fsX, S428L, S428X,
417 10
451 10 P451L,
531 10 R531Q, R531Del, R531W,
450 11
463 11 F463L, F463L, F463L,
462 11 M462Ins,
507 11 P507S, P507L,
423 11
422 12 A422T,
418 12
426 12 P426H,
504 12 A504V,
505 12 A505V,
427 12 Y427H, Y427C, Y427S,
527 13
464 13 I464X,
429 13 A429P, A429V,
419 13
449 13
508 13
526 13
529 13
416 13
506 14 I506V,
522 14 G522E,
432 14
524 14
509 14 D509N,
414 15 I414fsX,
413 15 L413P,
465 15