KCNH2 Variant N33T

Summary of observed carriers, functional annotations, and structural context for KCNH2 N33T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

34%

90% CI: 12.5% – 53.1%

4/13 effective observations

Total carriers

3

2 LQT2 · 1 unaffected

Functional studies

2

Publications with functional data

N33T has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 97% of WT with a standard error of 17%. 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-3.581 0.051 -1 0.851 62

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
11854117 2002 1 0 1
10973849 2000 2 0 2
14661677 2003 1 1
Literature, cohort, and gnomAD – 3 1 2 –
Variant features alone – 10 8 2 –

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 7.5 19.6 None None
21536673 Xeno 35 3.5 11.5 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)
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 N33T.
Neighbour residue Distance (Å) Observed variants
33 0 N33T
34 4 A34T,
32 5 A32T,
36 5 V36X,
124 5 M124T, M124R,
35 5 R35W,
39 6 C39R, C39X,
40 6
795 6 V795I,
123 6
42 7 I42N,
125 7
794 7 V794I, V794D,
796 7 V796L, V796L, V796Del,
31 8 I31S,
41 8 V41A,
122 9
38 10
64 10 C64R, C64Y,
37 10
797 10 A797T,
115 11 V115M,
15 11 L15V,
86 11 L86R,
798 11 I798fsX,
126 11
790 11
63 11 P63H,
12 11 N12D,
791 11 R791W, R791Q,
30 11 I30Del, I30T,
793 11 D793N,
121 11 A121fsX,
61 12 Q61R,
114 12 P114S,
788 12 E788K, E788D, E788D,
792 12
14 12
789 12
60 12 M60T,
127 12
43 12 Y43D, Y43C,
116 13 K116Q,
87 13 L87P,
65 13 T65P,
117 13
113 14 V113Del,
62 14 R62Q,
11 14 Q11L, Q11H, Q11H,
18 14 I18M,
112 14 V112M,
44 14 C44F, C44X, C44W,
89 14 A89G, A89V,
59 14
85 14 A85P, A85V,
29 15 F29L, F29V, F29S, F29L, F29L,
860 15
120 15
66 15 C66R, C66G, C66Y,