KCNH2 Variant D16A

Summary of observed carriers, functional annotations, and structural context for KCNH2 D16A. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

9%

0/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

1

Publications with functional data

D16A 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: 134% of WT with a standard error of 9%. 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 (%)
-3.024 0.021 -2 0.776 24

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 10 0 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Functional data

Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.

Homomeric channel data

Published electrophysiology measurements (homomeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
25417810 HEK293 59 13.2 None None 1.534131737

Heteromeric channel data

Published electrophysiology measurements (heteromeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
25417810 HEK293 None None None

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 D16A.
Neighbour residue Distance (Å) Observed variants
16 0 D16A,
17 4
19 5 I19F,
15 6 L15V,
20 6 R20L, R20G,
13 6 T13N,
786 6
18 7 I18M,
825 7
826 8 T826A, T826I,
14 8
785 8 G785fsX, G785D, G785S,
798 9 I798fsX,
12 9 N12D,
21 10
788 10 E788K, E788D, E788D,
43 10 Y43D, Y43C,
10 10
800 10
23 10
787 11
22 11 F22Y, F22S,
824 11
828 11
9 11 A9T, A9V,
801 11 K801T,
799 12 L799sp,
31 12 I31S,
765 12
827 12
29 12 F29L, F29L, F29S, F29V, F29L,
797 12 A797T,
11 13 Q11H, Q11L, Q11H,
42 13 I42N,
24 13
479 13
784 13 R784G, R784Q, R784W,
480 13 E480V,
795 13 V795I,
124 13 M124R, M124T,
45 13 N45K, N45D, N45K,
126 14
44 14 C44X, C44W, C44F,
766 14
25 14 Q25P,
115 14 V115M,
823 14 R823T, R823Q, R823fsX, R823W,
782 14 I782N, I782fsX,
764 14
829 14 D829E, D829E, D829A,
763 14
27 15 R27X, R27P,
789 15
783 15 S783P,
30 15 I30Del, I30T,
803 15 D803X, D803Y,
8 15
481 15