KCNH2 Variant E699D

Summary of observed carriers, functional annotations, and structural context for KCNH2 E699D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

10%

90% CI: 0.7% – 22.9%

1/12 effective observations

Total carriers

2

0 LQT2 · 4 unaffected

Functional studies

0

Publications with functional data

E699D is present in 2 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 80% of WT with a standard error of 29%. 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 (%)
-2.883 0.34 1 0.678 7

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 4 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 E699D.
Neighbour residue Distance (Å) Observed variants
699 0 E699D, E699D,
698 6 E698K, E698X,
695 6
6 6 G6R,
700 6
696 7 R696C, R696H,
7 7
702 7
697 7 L697X,
5 7
703 7
764 8
4 8
765 8
701 9
767 9 D767X,
766 9
481 9
704 10 A704T, A704V,
694 10 R694C, R694H,
693 10 L693X,
8 10
724 10 L724X,
692 11
827 11
763 11
720 11
706 11 S706C, S706F,
3 12
482 12 V482A,
476 12 V476I,
691 12
677 12 M677T,
680 12
478 12 A478D,
480 12 E480V,
721 12 P721L,
9 13 A9T, A9V
403 13
768 13
705 13 W705fsX, W705X,
824 13
762 13
727 13
10 13
723 13 C723R, C723G, C723X,
673 14
689 14
402 14 H402R,
690 14
719 14
479 14
707 14
681 14 R681W,
684 14
826 14 T826A, T826I,
477 14
728 14
828 15
825 15
823 15 R823W, R823fsX, R823T, R823Q,
708 15
769 15