KCNH2 Variant K28E

Summary of observed carriers, functional annotations, and structural context for KCNH2 K28E. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

17%

90% CI: 6.1% – 30.2%

3/24 effective observations

Total carriers

14

2 LQT2 · 12 unaffected

Functional studies

2

Publications with functional data

K28E has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 7%. 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 (%)
-2.22 0.43 0 0.865 53

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
15699249 2005 14 12 2
Literature, cohort, and gnomAD – 14 12 2 –
Variant features alone – 10 9 1 –

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)
15699249 HEK293 34 None -15.5 0.692307692 0.320809249
21536673 Xeno 10 -2.7 7.8 None 0.666666667

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)
15699249 HEK293 69 None None 0.919075145
21536673 Xeno 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 K28E.
Neighbour residue Distance (Å) Observed variants
28 0 K28E,
27 5 R27X, R27P,
129 5 F129C,
47 5 G47C, G47V,
128 6 N128S,
130 6 E130K,
48 6
29 6 F29L, F29V, F29S, F29L, F29L,
51 7
45 7 N45D, N45K, N45K,
26 7 S26I,
50 9 E50X,
131 9 V131L, V131L, V131fsX,
30 9 I30Del, I30T,
108 9 C108Y,
127 9
49 9 C49R, C49G,
22 9 F22Y, F22S,
46 10 D46Y, D46E, D46E,
25 10 Q25P,
109 10 L109X, L109Q, L109P,
52 10 C52W,
111 10 D111V,
110 10 V110A,
44 11 C44F, C44X, C44W,
23 11
106 11 F106L, F106V, F106L, F106L,
126 11
43 12 Y43D, Y43C,
98 12
24 12
53 12 G53S, G53R,
19 13 I19F,
100 13 R100G, R100Q, R100P,
31 13 I31S
107 13 L107P,
112 13 V112M,
69 13 L69Del, L69P,
21 14
113 14 V113Del,
56 14 R56Q,
59 14
93 14 K93X, K93R,
96 14 I96V, I96T,
54 14 Y54N, Y54X,
18 14 I18M,
66 14 C66R, C66G, C66Y,
97 15
94 15 V94L, V94L, V94A,
95 15 E95K, E95G,
55 15 S55L,
41 15 V41A,