KCNH2 Variant K741R

Summary of observed carriers, functional annotations, and structural context for KCNH2 K741R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

6%

90% CI: 0.5% – 26.1%

1/17 effective observations

Total carriers

7

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

K741R is present in 7 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 79% of WT with a standard error of 16%. 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 (%)
-2.218 0.102 2 0.643 21

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 – 7 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 K741R.
Neighbour residue Distance (Å) Observed variants
741 0 K741R,
742 5
740 5 C740G, C740W,
855 6 S855R, S855R, S855R,
744 6 R744G, R744fsX, R744X, R744Q, R744P,
856 7
857 7 E857X,
743 8
739 9 H739fsX,
802 9
745 10 G745A, G745X,
851 10
854 10
852 10
736 10
804 10
737 11 L737P,
55 11 S55L,
803 11 D803Y, D803X,
738 11 Q738X,
858 12 I858V, I858T,
781 12
56 12 R56Q,
746 12 A746S, A746X,
735 12 S735L,
853 13 W853X,
859 13 T859M, T859R
46 13 D46Y, D46E, D46E,
848 13
49 13 C49R, C49G,
57 13 A57P,
53 14 G53S, G53R,
782 14 I782fsX, I782N,
801 14 K801T,
58 14 E58K, E58D, E58D,
50 14 E50X,
783 15 S783P,
751 15 L751V,
800 15
849 15