KCNH2 Variant I18M

Summary of observed carriers, functional annotations, and structural context for KCNH2 I18M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

12%

90% CI: 1.1% – 30.0%

1/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

I18M is present in 1 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 109% of WT with a standard error of 22%. 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 (%)
-1.759 0.113 0 0.827 32

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 – 1 1 0 –
Variant features alone – 10 9 1 –

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 I18M.
Neighbour residue Distance (Å) Observed variants
18 0 I18M,
17 4
19 5 I19F,
15 6 L15V,
21 6
22 6 F22Y, F22S,
16 7 D16A,
14 7
126 8
20 8 R20G, R20L,
29 9 F29L, F29V, F29S, F29L, F29L,
31 9 I31S,
115 9 V115M,
13 9 T13N,
23 9
43 10 Y43D, Y43C,
124 10 M124T, M124R,
25 10 Q25P,
113 11 V113Del,
798 11 I798fsX,
24 11
27 11 R27X, R27P,
12 11 N12D,
30 11 I30Del, I30T,
128 12 N128S,
114 12 P114S,
786 12
127 12
45 12 N45D, N45K, N45K,
32 12 A32T,
42 12 I42N,
123 12
125 12
825 12
788 13 E788K, E788D, E788D,
26 13 S26I,
116 13 K116Q,
44 13 C44F, C44X, C44W,
111 14 D111V,
795 14 V795I,
785 14 G785S, G785fsX, G785D,
826 14 T826A, T826I,
10 14
112 14 V112M,
28 14 K28E,
33 14 N33T
800 14
117 14
797 14 A797T,
11 14 Q11L, Q11H, Q11H,
129 15 F129C,
122 15