KCNH2 Variant G785D

Summary of observed carriers, functional annotations, and structural context for KCNH2 G785D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

17%

90% CI: 14.8% – 54.9%

4/14 effective observations

Total carriers

4

3 LQT2 · 1 unaffected

Functional studies

1

Publications with functional data

G785D has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 1%. 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 (%)
-6.75 1.0 -2 0.983 54

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
Japan Cohort 2020 4 1 3
29146210 2018 3 2 1
Literature, cohort, and gnomAD – 4 1 3 –
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)
29146210 HEK293 None 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)
29146210 HEK293 47 5.3 -10.7 1.311068702

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 G785D.
Neighbour residue Distance (Å) Observed variants
785 0 G785S, G785fsX, G785D,
786 4
828 5
800 5
801 5 K801T,
826 6 T826A, T826I,
784 6 R784G, R784W, R784Q,
783 6 S783P,
829 7 D829A, D829E, D829E,
787 7
782 7 I782fsX, I782N,
825 8
799 8 L799sp,
16 8 D16A,
824 9
830 9
803 9 D803Y, D803X,
827 9
802 9
763 9
798 10 I798fsX,
20 10 R20G, R20L
19 10 I19F,
788 10 E788K, E788D, E788D,
762 11
765 11
764 11
43 11 Y43D, Y43C,
831 12
15 12 L15V,
13 12 T13N,
17 13
479 13
797 13 A797T,
805 13 F805S, F805C,
761 13
781 13
735 13 S735L,
23 13
804 13
56 13 R56Q,
767 13 D767X,
822 13 V822M, V822L, V822L,
766 13
789 14
46 14 D46Y, D46E, D46E,
44 14 C44F, C44X, C44W,
780 14
45 14 N45D, N45K, N45K,
769 14
823 14 R823W, R823fsX, R823T, R823Q,
18 14 I18M,
10 14
736 14
859 14 T859M, T859R,
12 14 N12D,
760 15
42 15 I42N,