KCNH2 Variant E90K

Summary of observed carriers, functional annotations, and structural context for KCNH2 E90K. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

8%

90% CI: 0.5% – 22.4%

1/13 effective observations

Total carriers

3

0 LQT2 · 3 unaffected

Functional studies

1

Publications with functional data

E90K is present in 3 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 87% of WT with a standard error of 16%. 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 (%)
-2.382 0.409 1 0.698 17

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
29752375 2018 1 0 SIDS
Literature, cohort, and gnomAD – 3 3 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)
29752375 HEK293 111 4.0 None None 1.0

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)
29752375 HEK293 100 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 E90K.
Neighbour residue Distance (Å) Observed variants
90 0 E90K,
89 4 A89G, A89V,
92 5 R92C, R92L,
91 5
88 6
114 6 P114S,
85 6 A85P, A85V,
112 7 V112M,
113 7 V113Del,
86 8 L86R,
87 9 L87P,
125 10
111 10 D111V,
116 10 K116Q,
122 10
93 10 K93X, K93R,
115 10 V115M,
84 10
82 11 I82Del, I82dup, I82Ins, I82T,
126 11
83 11 A83P, A83fsX,
94 11 V94L, V94L, V94A,
81 12 Q81E, Q81X, Q81P, Q81H, Q81H,
110 12 V110A,
127 12
121 12 A121fsX,
124 13 M124T, M124R,
123 13
120 13
128 14 N128S,
80 14 A80P,
34 14 A34T,
32 14 A32T
64 14 C64R, C64Y,
109 15 L109X, L109Q, L109P,
117 15