KCNH2 Variant R744Q

Summary of observed carriers, functional annotations, and structural context for KCNH2 R744Q. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

13%

90% CI: 5.1% – 39.3%

2/19 effective observations

Total carriers

9

1 LQT2 · 2 unaffected

Functional studies

0

Publications with functional data

R744Q is present in 8 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 120% of WT with a standard error of 3%. 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 (%)
-1.807 0.446 1 0.601 23

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 0 1
Literature, cohort, and gnomAD – 9 2 1 –
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 R744Q.
Neighbour residue Distance (Å) Observed variants
744 0 R744G, R744fsX, R744X, R744Q, R744P,
745 6 G745A, G745X,
740 6 C740G, C740W,
741 6 K741R,
742 6
743 7
738 7 Q738X,
739 8 H739fsX,
737 8 L737P,
746 8 A746S, A746X,
855 10 S855R, S855R, S855R,
851 10
736 10
751 11 L751V,
735 11 S735L,
852 11
747 12
848 12
856 12
802 12
748 13
750 13 C750X,
854 13
857 13 E857X
734 14 R734C, R734H,
730 14
733 14
781 14
754 14
749 15
804 15