KCNH2 Variant G745A

Summary of observed carriers, functional annotations, and structural context for KCNH2 G745A. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

10%

1/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

G745A has not been reported in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 116% of WT with a standard error of 31%. 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 (%)
-5.769 0.63 0 0.739 9

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
26746457 2016 1 1
Literature, cohort, and gnomAD – 1 1 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 G745A.
Neighbour residue Distance (Å) Observed variants
745 0 G745A, G745X,
746 3 A746S, A746X,
851 6
744 6 R744G, R744fsX, R744X, R744Q, R744P,
742 6
848 7
743 7
747 7
852 9
750 9 C750X,
855 9 S855R, S855R, S855R,
751 9 L751V,
741 10 K741R,
737 10 L737P,
847 10
740 10 C740G, C740W,
748 10
849 10
850 11 D850N,
749 11
854 11
845 11
856 12
738 12 Q738X,
754 12
846 12 P846T, P846S,
853 13 W853X,
842 13
736 13
739 13 H739fsX,
773 14
753 14 A753S,
841 14 V841L, V841L,
772 14
752 15 R752W, R752Q, R752P,
857 15 E857X
730 15