KCNH2 Variant E130K

Summary of observed carriers, functional annotations, and structural context for KCNH2 E130K. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

11%

1/13 effective observations

Total carriers

3

0 LQT2 · 2 unaffected

Functional studies

1

Publications with functional data

E130K is present in 2 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 67% of WT with a standard error of 20%. 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 (%)
-2.716 0.812 -2 0.882 23

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
Japan Cohort 2020 1 1 0
15090700 2004 1 0 1
Literature, cohort, and gnomAD – 3 2 0 –
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)
25417810 HEK293 44 -11.1 None None 1.104191617

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 E130K.
Neighbour residue Distance (Å) Observed variants
130 0 E130K,
131 4 V131L, V131L, V131fsX,
109 6 L109X, L109Q, L109P,
28 6 K28E,
108 6 C108Y,
129 6 F129C,
128 7 N128S,
27 8 R27X, R27P,
110 9 V110A,
107 9 L107P,
111 9 D111V,
51 10
26 10 S26I,
106 10 F106L, F106V, F106L, F106L,
93 11 K93X, K93R,
47 11 G47C, G47V,
95 11 E95K, E95G,
25 11 Q25P,
29 11 F29L, F29V, F29S, F29L, F29L,
48 11
127 12
98 12
94 12 V94L, V94L, V94A,
96 12 I96V, I96T,
22 12 F22Y, F22S,
50 13 E50X,
97 13
45 13 N45D, N45K, N45K,
112 13 V112M,
30 13 I30Del, I30T
52 14 C52W,
100 14 R100G, R100Q, R100P,
126 14
105 14
113 14 V113Del,
24 14
23 15
49 15 C49R, C49G,