KCNH2 Variant N12D

Summary of observed carriers, functional annotations, and structural context for KCNH2 N12D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

9%

90% CI: 0.5% – 26.2%

1/12 effective observations

Total carriers

2

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

N12D is present in 2 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 103% of WT with a standard error of 19%. 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 (%)
-2.769 0.081 0 0.683 12

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 – 2 1 0 –
Variant features alone – 10 9 1 –

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 N12D.
Neighbour residue Distance (Å) Observed variants
12 0 N12D,
11 4 Q11L, Q11H, Q11H,
13 5 T13N,
14 5
10 6
15 6 L15V,
788 7 E788K, E788D, E788D,
795 7 V795I,
825 7
9 9 A9T, A9V,
823 9 R823W, R823fsX, R823T, R823Q,
790 9
16 9 D16A,
824 10
793 10 D793N,
124 10 M124T, M124R,
794 10 V794I, V794D,
798 10 I798fsX,
123 10
797 10 A797T,
786 10
17 11
766 11
789 11
796 11 V796L, V796L, V796Del,
33 11 N33T
18 11 I18M,
42 11 I42N,
787 11
826 11 T826A, T826I,
765 12
8 12
31 12 I31S,
117 12
792 12
19 12 I19F,
115 12 V115M,
822 13 V822M, V822L, V822L,
32 13 A32T,
7 13
821 13 D821E, D821E,
799 13 L799sp,
43 13 Y43D, Y43C,
35 13 R35W,
767 14 D767X,
34 14 A34T,
785 14 G785S, G785fsX, G785D,
768 14
121 14 A121fsX,
122 14
828 14
791 15 R791W, R791Q,
764 15
116 15 K116Q,
118 15 E118K, E118X, E118D, E118D,
36 15 V36X,
800 15
125 15
126 15