KCNH2 Variant N861I

Summary of observed carriers, functional annotations, and structural context for KCNH2 N861I. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

41%

5/13 effective observations

Total carriers

3

3 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

N861I has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 63% 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 (%)
-7.53 0.996 -4 0.925 90

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
11854117 2002 3 0 3
10973849 2000 1 0 1
Literature, cohort, and gnomAD – 3 0 3 –
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 N861I.
Neighbour residue Distance (Å) Observed variants
861 0 N861H, N861I,
862 4 L862P,
807 5 E807X,
806 6 G806R, G806R,
860 6
858 6 I858V, I858T,
808 7
863 8 R863X, R863P
859 8 T859M, T859R,
819 8 N819K, N819K,
61 9 Q61R,
57 9 A57P,
805 9 F805S, F805C,
812 9 Y812S,
818 10 S818A, S818W, S818L,
776 10 L776I, L776P,
816 10 G816V,
804 10
811 10
60 11 M60T,
820 11 G820R, G820R,
857 11 E857X,
809 11
779 11
789 11
817 12
856 12
810 12
778 12 A778T,
58 12 E58K, E58D, E58D,
797 13 A797T,
796 13 V796L, V796L, V796Del,
780 13
791 13 R791W, R791Q,
853 13 W853X,
799 13 L799sp,
62 13 R62Q,
803 13 D803Y, D803X,
56 13 R56Q,
815 14
770 14
822 14 V822M, V822L, V822L,
59 14
773 14
55 14 S55L,
835 14 R835W, R835fsX, R835Q,
774 14 D774Y, D774X,
772 14
777 14
775 14
821 14 D821E, D821E,
781 14
813 14
790 15
41 15 V41A,
42 15 I42N,