KCNH2 Variant A746S

Summary of observed carriers, functional annotations, and structural context for KCNH2 A746S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

9%

1/13 effective observations

Total carriers

3

0 LQT2 · 3 unaffected

Functional studies

0

Publications with functional data

A746S is present in 3 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 28% of WT with a standard error of 5%. 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 (%)
-2.026 0.243 3 0.682 5

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 – 3 3 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 A746S.
Neighbour residue Distance (Å) Observed variants
746 0 A746S, A746X,
745 3 G745A, G745X,
747 4
750 6 C750X,
848 6
751 7 L751V,
748 7
743 7
749 8
851 8
744 8 R744G, R744fsX, R744X, R744Q, R744P,
742 8
737 9 L737P,
845 9
847 10
852 10
754 10
773 11
849 11
772 11
753 11 A753S,
752 12 R752W, R752Q, R752P,
738 12 Q738X,
740 12 C740G, C740W,
846 12 P846T, P846S,
855 12 S855R, S855R, S855R
842 12
741 12 K741R,
841 12 V841L, V841L,
774 12 D774Y, D774X,
850 13 D850N,
730 13
736 13
755 13
817 13
771 14 H771fsX, H771R,
856 14
739 14 H739fsX,
854 14
853 14 W853X,
844 14 M844V,
818 15 S818A, S818W, S818L,
733 15
838 15 L838R,