KCNH2 Variant D850N

Summary of observed carriers, functional annotations, and structural context for KCNH2 D850N. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

6%

90% CI: 0.3% – 21.7%

0/14 effective observations

Total carriers

4

0 LQT2 · 2 unaffected

Functional studies

0

Publications with functional data

D850N is present in 4 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 105% of WT with a standard error of 6%. 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 0 individuals with LQT2 and 10 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-3.689 0.573 1 0.52 14

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 – 4 2 0 –
Variant features alone – 10 10 0 –

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 D850N.
Neighbour residue Distance (Å) Observed variants
850 0 D850N,
849 4
851 6
846 7 P846T, P846S,
848 7
847 7
854 7
853 8 W853X,
852 8
842 9
855 10 S855R, S855R, S855R,
810 10
745 11 G745A, G745X,
856 11
845 11
742 12
843 12
746 13 A746S, A746X,
809 13
841 13 V841L, V841L,
839 13
750 14 C750X,
844 14 M844V,
743 14
838 14 L838R,
811 14
747 14
808 14
857 15 E857X