KCNH2 Variant G53R

Summary of observed carriers, functional annotations, and structural context for KCNH2 G53R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

39%

6/18 effective observations

Total carriers

8

3 LQT2 · 0 unaffected

Functional studies

2

Publications with functional data

G53R 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 6%. 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 3 individuals with LQT2 and 7 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-5.081 0.996 -4 0.934 79

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
24103226 2014 1 0 1 Seizures
10973849 2000 1 0 1
15840476 2005 1 0 1
Personal Communication 2022 6 0 1 Seizures
Literature, cohort, and gnomAD – 8 0 3 –
Variant features alone – 10 7 3 –

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)
10187793 Xeno None None None None
21536673 Xeno 5 None None None None

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)
10187793 Xeno None None None
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 G53R.
Neighbour residue Distance (Å) Observed variants
53 0 G53S, G53R,
52 4 C52W,
54 4 Y54X, Y54N,
49 5 C49R, C49G,
101 5 K101E,
55 6 S55L,
51 7
100 7 R100P, R100G, R100Q,
50 7 E50X,
48 8
102 8 D102V, D102H, D102X,
58 8 E58K, E58D, E58D,
47 9 G47C, G47V,
59 10
68 10 F68L, F68L, F68V, F68L,
69 10 L69P, L69Del,
104 10
46 10 D46E, D46Y, D46E,
103 11
56 11 R56Q,
44 11 C44X, C44W, C44F,
57 11 A57P,
106 11 F106L, F106L, F106L, F106V,
45 11 N45K, N45D, N45K,
857 12 E857X,
99 12 Y99N, Y99S,
98 12
28 12 K28E,
105 13
66 13 C66G, C66Y, C66R,
60 13 M60T,
129 14 F129C,
741 14 K741R,
62 14 R62Q,
30 14 I30Del, I30T,
70 15 H70Q, H70R, H70Q,
29 15 F29S, F29L, F29V, F29L, F29L,
43 15 Y43C, Y43D,
859 15 T859M, T859R,
108 15 C108Y,