KCNH2 Variant I858T

Summary of observed carriers, functional annotations, and structural context for KCNH2 I858T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

38%

90% CI: 16.2% – 62.3%

4/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

I858T has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 2% of WT with a standard error of 5%. 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 3 individuals with LQT2 and 7 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-4.09 0.987 -1 0.96 52

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
24606995 2014 1 0 1
Literature, cohort, and gnomAD – 1 0 1 –
Variant features alone – 10 7 3 –

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 I858T.
Neighbour residue Distance (Å) Observed variants
858 0 I858V, I858T,
859 5 T859M, T859R,
804 5
857 6 E857X,
806 6 G806R, G806R,
856 6
861 6 N861H, N861I,
808 7
57 7 A57P,
860 7
805 8 F805S, F805C,
807 8 E807X,
779 8
803 9 D803Y, D803X,
862 9 L862P,
853 9 W853X,
781 10
56 10 R56Q,
855 10 S855R, S855R, S855R,
55 10 S55L,
60 11 M60T,
780 11
809 11
852 11
58 11 E58K, E58D, E58D,
799 11 L799sp,
854 11
741 12 K741R,
61 12 Q61R,
742 12
782 12 I782fsX, I782N,
810 12
778 12 A778T,
811 12
802 12
776 12 L776I, L776P,
740 13 C740G, C740W,
59 13
800 13
789 13
812 13 Y812S,
797 13 A797T,
833 13
743 14
44 14 C44F, C44X, C44W,
819 14 N819K, N819K,
787 14
838 14 L838R,
816 14 G816V,
863 14 R863X, R863P
835 14 R835W, R835fsX, R835Q,
736 14
818 14 S818A, S818W, S818L,
798 15 I798fsX,
62 15 R62Q,
820 15 G820R, G820R,
822 15 V822M, V822L, V822L,
777 15
831 15
796 15 V796L, V796L, V796Del,
832 15