KCNH2 Variant R784W

Summary of observed carriers, functional annotations, and structural context for KCNH2 R784W. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

6%

2/22 effective observations

Total carriers

12

1 LQT2 · 4 unaffected

Functional studies

1

Publications with functional data

R784W is present in 10 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 37% of WT with a standard error of 15%. 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 (%)
-7.715 1.0 -3 0.944 15

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
11997281 2002 1 1
15840476 2005 1 0 1
Literature, cohort, and gnomAD – 12 4 1 –
Variant features alone – 10 9 1 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Functional data

Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.

Homomeric channel data

Published electrophysiology measurements (homomeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
11997281 CHO 25 13.3 None None None

Heteromeric channel data

Published electrophysiology measurements (heteromeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
11997281 CHO None None None

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 R784W.
Neighbour residue Distance (Å) Observed variants
784 0 R784G, R784W, R784Q,
783 4 S783P,
829 4 D829A, D829E, D829E,
785 6 G785S, G785fsX, G785D,
801 7 K801T,
828 7
782 8 I782fsX, I782N,
830 9
735 9 S735L,
826 9 T826A, T826I,
800 9
762 9
802 10
786 10
827 10
831 10
763 11
734 11 R734C, R734H,
736 11
803 12 D803Y, D803X,
787 12
761 12
760 12
739 12 H739fsX,
20 12 R20G, R20L
479 12
707 12
781 13
733 13
764 13
799 13 L799sp,
732 13
825 13
824 13
16 13 D16A,
688 13
687 14
765 14
740 14 C740G, C740W,
686 14
731 14 H731R,
738 14 Q738X,
703 15
19 15 I19F,
804 15
478 15 A478D,