KCNH2 Variant A478G

Summary of observed carriers, functional annotations, and structural context for KCNH2 A478G. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

21%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

A478G has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 129% of WT with a standard error of 27%. 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 (%)
-1.698 0.153 -1 0.521 16

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 A478G.
Neighbour residue Distance (Å) Observed variants
478 0 A478D,
479 4
477 4
480 5 E480V,
476 7 V476I,
481 7
827 8
4 9
475 9 Y475C, Y475Del,
482 9 V482A,
703 9
6 10 G6R,
706 10 S706C, S706F,
483 10 V483I,
492 11 H492Y,
765 11
702 11
826 12 T826A, T826I,
764 12
707 12
699 12 E699D, E699D,
7 13
704 13 A704T, A704V,
5 13
8 13
9 14 A9T, A9V
488 14 R488C, R488H,
474 14 T474I,
762 14
402 14 H402R,
828 14
763 14
705 14 W705fsX, W705X,
3 14
484 14
489 14 I489F, I489I,
829 15 D829A, D829E, D829E,
709 15
825 15
491 15 V491I,
784 15 R784G, R784W, R784Q,
700 15