KCNH2 Variant E481D

Summary of observed carriers, functional annotations, and structural context for KCNH2 E481D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

16%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

E481D has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 98% 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 1 individuals with LQT2 and 9 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-2.78 0.998 1 0.827 49

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 E481D.
Neighbour residue Distance (Å) Observed variants
481 0
482 4 V482A,
480 4 E480V,
6 4 G6R,
476 6 V476I,
477 6
478 7 A478D,
7 7
8 7
483 7 V483I,
479 7
9 8 A9T, A9V,
4 8
765 8
475 8 Y475C, Y475Del,
5 9
827 9
699 9 E699D, E699D,
402 10 H402R,
474 10 T474I,
484 10
10 11
764 11
703 11
826 11 T826A, T826I,
702 11
403 12
766 12
488 12 R488C, R488H,
695 12
13 12 T13N,
825 12
3 13
401 13
492 13 H492Y,
767 13 D767X,
706 13 S706C, S706F,
698 13 E698K, E698X,
489 13 I489F, I489I,
824 13
763 14
485 14 H485X,
700 14
473 14 T473P,
696 14 R696C, R696H,
828 14
704 15 A704T, A704V,
11 15 Q11L, Q11H, Q11H,
16 15 D16A