KCNH2 Variant M133T

Summary of observed carriers, functional annotations, and structural context for KCNH2 M133T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

4%

0/18 effective observations

Total carriers

8

0 LQT2 · 3 unaffected

Functional studies

0

Publications with functional data

M133T is present in 8 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 125% of WT with a standard error of 9%. 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 0 individuals with LQT2 and 10 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-0.525 0.0 3 0.438 4

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
Literature, cohort, and gnomAD – 8 3 0 –
Variant features alone – 10 10 0 –

Totals may differ from individual publications due to duplicate patients removed during curation.

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 M133T.
Neighbour residue Distance (Å) Observed variants
133 0 M133T,
132 4 V132X,
134 4 E134X,
131 5 V131fsX, V131L, V131L,
135 5
130 7 E130K,
136 7
129 8 F129C,
137 8
128 8 N128S,
138 8
127 9
139 9 G139R, G139A, G139R,
126 10
140 10 S140Y,
125 11
141 11 P141fsX, P141S, P141L,
124 11 M124T, M124R,
142 11 A142T,
123 12
143 12
122 13
144 13 D144V,
121 13 A121fsX,
145 13
120 14
146 14 N146X,
119 14 D119G, D119H,
147 14 H147R, H147X,
118 15 E118K, E118D, E118X, E118D
148 15 R148fsX, R148Q, R148Y, R148W,