KCNH2 Variant C740W

Summary of observed carriers, functional annotations, and structural context for KCNH2 C740W. 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

C740W is present in 1 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 96% 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 (%)
-10.683 0.997 -3 0.855 7

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 – 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 C740W.
Neighbour residue Distance (Å) Observed variants
740 0 C740G, C740W,
741 5 K741R,
739 5 H739fsX,
736 5
743 6
742 6
744 6 R744G, R744fsX, R744X, R744Q, R744P,
737 7 L737P,
802 7
735 7 S735L,
738 7 Q738X,
781 8
856 9
804 9
855 10 S855R, S855R, S855R,
803 10 D803Y, D803X,
745 10 G745A, G745X,
783 10 S783P,
857 11 E857X,
852 11
782 11 I782fsX, I782N,
733 11
831 11
801 11 K801T,
734 12 R734C, R734H,
751 12 L751V,
746 12 A746S, A746X,
851 12
858 13 I858V, I858T,
758 13
754 13
800 13
848 13
779 13
859 13 T859M, T859R
56 13 R56Q,
730 13
854 13
46 14 D46Y, D46E, D46E,
853 14 W853X,
755 14
784 14 R784G, R784W, R784Q,
830 14
805 14 F805S, F805C,
750 14 C750X,
55 14 S55L,
833 15
780 15
732 15
799 15 L799sp,
747 15