KCNH2 Variant D46N

Summary of observed carriers, functional annotations, and structural context for KCNH2 D46N. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

18%

1/11 effective observations

Total carriers

1

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

D46N is present in 1 alleles in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 153% of WT with a standard error of 28%. 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 (%)
-3.005 0.852 1 0.825 47

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 – 1 0 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 D46N.
Neighbour residue Distance (Å) Observed variants
46 0 D46Y, D46E, D46E,
45 5 N45D, N45K, N45K,
47 5 G47C, G47V,
49 6 C49R, C49G,
50 6 E50X,
44 7 C44F, C44X, C44W,
56 8 R56Q,
48 8
43 9 Y43D, Y43C,
802 9
801 9 K801T,
29 10 F29L, F29V, F29S, F29L, F29L,
27 10 R27X, R27P,
28 10 K28E,
55 10 S55L,
800 10
23 10
26 10 S26I,
53 10 G53S, G53R,
51 11
803 11 D803Y, D803X,
52 11 C52W,
19 12 I19F,
30 12 I30Del, I30T,
59 12
799 13 L799sp,
741 13 K741R,
54 13 Y54N, Y54X,
798 13 I798fsX,
24 13
22 13 F22Y, F22S,
60 13 M60T,
129 13 F129C,
859 13 T859M, T859R,
57 13 A57P,
739 13 H739fsX,
740 14 C740G, C740W,
785 14 G785S, G785fsX, G785D,
857 14 E857X,
31 14 I31S
782 14 I782fsX, I782N,
25 14 Q25P,
58 14 E58K, E58D, E58D,
783 14 S783P,
128 14 N128S,
804 14
786 15
42 15 I42N,
20 15 R20G, R20L,
41 15 V41A,