KCNH2 Variant D821E

Summary of observed carriers, functional annotations, and structural context for KCNH2 D821E. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

15%

90% CI: 2.2% – 34.7%

1/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

D821E is present in 1 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 97% of WT with a standard error of 15%. 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 (%)
-3.355 0.563 2 0.586 38

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 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 D821E.
Neighbour residue Distance (Å) Observed variants
821 0 D821E, D821E,
820 4 G820R, G820R,
771 5 H771fsX, H771R,
822 5 V822M, V822L, V822L,
790 5
772 6
770 6
823 6 R823W, R823fsX, R823T, R823Q,
789 7
768 7
791 8 R791W, R791Q,
819 8 N819K, N819K,
792 8
818 8 S818A, S818W, S818L,
769 9
774 9 D774Y, D774X,
773 9
793 9 D793N,
794 10 V794I, V794D,
748 10
788 10 E788K, E788D, E788D,
862 10 L862P,
796 10 V796L, V796L, V796Del,
797 11 A797T,
795 11 V795I,
824 11
749 11
767 11 D767X,
787 11
723 11 C723R, C723G, C723X,
766 11
752 11 R752W, R752Q, R752P,
860 12
805 12 F805S, F805C,
776 12 L776I, L776P,
747 12
806 13 G806R, G806R,
817 13
780 13
12 13 N12D
799 13 L799sp,
775 13
825 14
863 14 R863X, R863P,
798 14 I798fsX,
11 14 Q11L, Q11H, Q11H,
750 14 C750X,
861 14 N861H, N861I,
727 14
778 14 A778T,
726 15
816 15 G816V,
763 15
10 15
724 15 L724X,
696 15 R696C, R696H,
751 15 L751V,
42 15 I42N,
722 15
807 15 E807X,
786 15