KCNH2 Variant R791W

Summary of observed carriers, functional annotations, and structural context for KCNH2 R791W. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

2%

90% CI: 0.2% – 8.7%

1/70 effective observations

Total carriers

60

0 LQT2 · 26 unaffected

Functional studies

2

Publications with functional data

R791W is present in 59 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 66% of WT with a standard error of 13%. 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 (%)
-6.566 1.0 -3 0.881 9

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
Italy Cohort 2020 1 1 0
29752375 2018 1 0 SIDS
Literature, cohort, and gnomAD – 60 26 0 –
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)
25417810 HEK293 107 -12.2 None None 0.74251497
29752375 HEK293 83 6.0 None None 0.666666667

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)
25417810 HEK293 None None None
29752375 HEK293 100 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 R791W.
Neighbour residue Distance (Å) Observed variants
791 0 R791W, R791Q,
819 5 N819K, N819K,
794 6 V794I, V794D,
792 6
820 6 G820R, G820R,
790 6
796 7 V796L, V796L, V796Del,
821 8 D821E, D821E,
789 8
795 9 V795I,
793 9 D793N,
772 9
36 9 V36X,
818 10 S818A, S818W, S818L,
797 10 A797T,
862 10 L862P,
61 10 Q61R,
860 10
863 11 R863X, R863P,
822 11 V822M, V822L, V822L,
37 11
35 11 R35W,
40 11
33 11 N33T
823 12 R823W, R823fsX, R823T, R823Q,
773 12
788 12 E788K, E788D, E788D,
42 12 I42N,
771 12 H771fsX, H771R,
770 12
861 13 N861H, N861I,
774 13 D774Y, D774X,
38 13
34 13 A34T,
60 13 M60T,
41 13 V41A,
817 14
39 14 C39R, C39X,
798 14 I798fsX,
748 14
806 14 G806R, G806R,
32 14 A32T,
12 15 N12D,
747 15
799 15 L799sp,
805 15 F805S, F805C,
768 15
787 15