KCNH2 Variant D829A

Summary of observed carriers, functional annotations, and structural context for KCNH2 D829A. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

7%

0/14 effective observations

Total carriers

4

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

D829A 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: 101% of WT with a standard error of 13%. 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 (%)
-7.385 0.999 -2 0.905 11

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 1 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 D829A.
Neighbour residue Distance (Å) Observed variants
829 0 D829A, D829E, D829E,
784 4 R784G, R784W, R784Q,
828 5
783 5 S783P,
830 5
762 5
785 7 G785S, G785fsX, G785D,
763 7
782 7 I782fsX, I782N,
831 7
761 8
827 8
760 8
826 9 T826A, T826I,
801 9 K801T,
764 10
786 10
707 10
735 10 S735L,
800 10
787 10
824 11
781 11
802 11
736 11
733 12
732 12
703 12
765 12
803 12 D803Y, D803X,
825 12
780 12
832 12
734 12 R734C, R734H,
799 12 L799sp,
687 12
767 12 D767X,
686 13
769 13
479 13
759 13 K759N, K759N,
805 13 F805S, F805C,
704 13 A704T, A704V,
758 14
688 14
766 14
804 14
708 14
731 14 H731R,
706 14 S706C, S706F,
700 14
739 14 H739fsX,
16 14 D16A
478 15 A478D,
822 15 V822M, V822L, V822L,
788 15 E788K, E788D, E788D,