KCNH2 Variant T859M

Summary of observed carriers, functional annotations, and structural context for KCNH2 T859M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

23%

2/10 effective observations

Total carriers

0

0 LQT2 · 54 unaffected

Functional studies

0

Publications with functional data

T859M has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 65% of WT with a standard error of 12%. 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
None None None 0.255 29

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
Literature, cohort, and gnomAD – 0 54 0 –
Variant features alone – 10 8 2 –

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 T859M.
Neighbour residue Distance (Å) Observed variants
859 0 T859M, T859R,
858 5 I858V, I858T,
860 5
804 5
57 5 A57P,
56 6 R56Q,
803 6 D803Y, D803X,
60 7 M60T,
799 7 L799sp,
805 7 F805C, F805S,
857 7 E857X,
861 8 N861H, N861I,
806 8 G806R, G806R,
55 9 S55L,
61 9 Q61R,
797 9 A797T
44 9 C44X, C44W, C44F,
800 9
862 10 L862P,
59 10
856 10
58 10 E58K, E58D, E58D,
782 10 I782N, I782fsX,
789 10
798 10 I798fsX,
781 10
802 10
787 11
42 11 I42N,
779 11
807 11 E807X,
43 11 Y43C, Y43D,
808 11
796 11 V796L, V796L, V796Del,
780 11
41 11 V41A,
62 12 R62Q,
741 13 K741R,
801 13 K801T,
49 13 C49R, C49G,
788 13 E788D, E788D, E788K,
822 13 V822L, V822L, V822M,
819 13 N819K, N819K,
855 13 S855R, S855R, S855R,
740 13 C740G, C740W,
46 13 D46E, D46Y, D46E,
786 13
45 14 N45K, N45D, N45K,
820 14 G820R, G820R,
40 14
54 14 Y54X, Y54N,
778 14 A778T,
783 14 S783P,
853 14 W853X,
776 14 L776I, L776P,
742 14
785 14 G785S, G785fsX, G785D,
830 14
790 14
854 15
31 15 I31S,
48 15
852 15
818 15 S818L, S818W, S818A,
795 15 V795I,
770 15
53 15 G53S, G53R,
736 15