KCNH2 Variant M124T

Summary of observed carriers, functional annotations, and structural context for KCNH2 M124T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

50%

90% CI: 39.9% – 72.0%

14/25 effective observations

Total carriers

15

12 LQT2 · 3 unaffected

Functional studies

2

Publications with functional data

M124T has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 95% 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-4.462 0.529 -3 0.941 66

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
19371231 2009 6 1 5
France Cohort 2020 5 1 4
15043509 2004 4 1 3
Literature, cohort, and gnomAD – 15 3 12 –
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)
15043509 Xeno 28 -2.7 None None 1.0
19371231 CHO 50 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)
15043509 Xeno 47 None None None
19371231 CHO 49 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 M124T.
Neighbour residue Distance (Å) Observed variants
124 0 M124T, M124R,
123 4
32 5 A32T,
33 5 N33T
125 5
115 6 V115M,
31 6 I31S,
34 6 A34T,
122 7
126 7
15 8 L15V,
114 8 P114S,
795 8 V795I,
14 8
42 8 I42N,
35 9 R35W,
116 9 K116Q,
121 9 A121fsX,
39 9 C39R, C39X,
113 10 V113Del,
40 10
12 10 N12D,
18 10 I18M,
36 10 V36X,
117 10
30 10 I30Del, I30T,
41 10 V41A,
127 10
796 11 V796L, V796L, V796Del,
794 11 V794I, V794D,
86 11 L86R,
64 11 C64R, C64Y,
798 11 I798fsX,
43 11 Y43D, Y43C,
112 12 V112M,
797 12 A797T,
89 12 A89G, A89V,
29 12 F29L, F29V, F29S, F29L, F29L,
19 12 I19F,
788 12 E788K, E788D, E788D,
120 12
13 12 T13N,
11 13 Q11L, Q11H, Q11H,
17 13
90 13 E90K,
16 13 D16A,
85 13 A85P, A85V,
87 14 L87P,
790 14
22 14 F22Y, F22S,
793 14 D793N,
38 14
88 14
118 14 E118K, E118X, E118D, E118D,
119 14 D119H, D119G,
128 14 N128S,
111 14 D111V,
63 14 P63H,
44 14 C44F, C44X, C44W,
60 14 M60T,
789 14
37 14
65 15 T65P,