KCNH2 Variant T826I

Summary of observed carriers, functional annotations, and structural context for KCNH2 T826I. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

13%

90% CI: 13.3% – 52.6%

4/15 effective observations

Total carriers

5

3 LQT2 · 1 unaffected

Functional studies

1

Publications with functional data

T826I is present in 1 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 6% of WT with a standard error of 6%. 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 (%)
-5.149 1.0 -1 0.958 39

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 2 0 2
Literature, cohort, and gnomAD – 5 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 1.5 -1.7 0.988549618

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 T826I.
Neighbour residue Distance (Å) Observed variants
826 0 T826A, T826I,
825 4
828 5
827 5
786 5
785 6 G785S, G785fsX, G785D,
765 6
824 6
764 7
763 7
16 8 D16A,
787 8
829 9 D829A, D829E, D829E,
13 9 T13N,
479 9
766 9
784 9 R784G, R784W, R784Q,
10 9
788 10 E788K, E788D, E788D,
767 10 D767X,
800 10
9 10 A9T, A9V,
762 10
480 10 E480V,
20 10 R20G, R20L
830 11
801 11 K801T,
783 11 S783P,
481 11
782 11 I782fsX, I782N,
17 11
799 11 L799sp,
15 11 L15V,
823 11 R823W, R823fsX, R823T, R823Q,
12 11 N12D,
798 12 I798fsX,
7 12
478 12 A478D,
703 12
19 12 I19F,
8 12
822 13 V822M, V822L, V822L,
769 13
14 13
761 13
477 13
768 13
482 13 V482A,
11 13 Q11L, Q11H, Q11H,
6 14 G6R,
797 14 A797T,
699 14 E699D, E699D,
803 14 D803Y, D803X,
789 14
18 14 I18M,
707 14
43 15 Y43D, Y43C,
700 15
831 15
802 15