KCNH2 Variant I42S

Summary of observed carriers, functional annotations, and structural context for KCNH2 I42S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

29%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

I42S 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 1%. 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 (%)
-3.882 0.846 -3 0.914 75

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 – 0 0 0 –
Variant features alone – 10 8 2 –

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 I42S.
Neighbour residue Distance (Å) Observed variants
42 0 I42N,
41 5 V41A,
797 5 A797T,
31 5 I31S,
798 5 I798fsX,
796 5 V796L, V796L, V796Del,
32 6 A32T,
40 6
43 6 Y43C, Y43D,
795 6 V795I,
60 6 M60T,
33 7 N33T,
44 8 C44W, C44F, C44X,
30 8 I30Del, I30T,
788 8 E788D, E788D, E788K,
124 8 M124R, M124T,
61 8 Q61R,
789 8
799 9 L799sp,
15 9 L15V,
39 10 C39X, C39R,
59 10
860 10
794 10 V794D, V794I,
56 10 R56Q,
36 10 V36X,
125 10
64 10 C64Y, C64R,
790 10
29 11 F29L, F29L, F29S, F29V, F29L,
34 11 A34T,
126 11
859 11 T859R, T859M,
19 11 I19F,
63 11 P63H,
787 11
12 11 N12D,
62 11 R62Q,
127 11
800 11
45 12 N45D, N45K, N45K,
123 12
786 12
35 12 R35W,
791 12 R791Q, R791W,
57 12 A57P,
14 12
18 12 I18M,
16 13 D16A,
48 13
38 13
803 13 D803X, D803Y,
825 13
822 14 V822M, V822L, V822L,
115 14 V115M,
66 14 C66G, C66R, C66Y,
55 14 S55L,
823 14 R823fsX, R823T, R823Q, R823W,
13 14 T13N,
37 14
65 14 T65P,
820 14 G820R, G820R,
819 14 N819K, N819K,
58 14 E58D, E58D, E58K,
793 14 D793N,
792 14
805 14 F805S, F805C,
49 14 C49G, C49R,
824 15
122 15
17 15
821 15 D821E, D821E,
785 15 G785S, G785fsX, G785D,
46 15 D46Y, D46E, D46E,
22 15 F22S, F22Y,
114 15 P114S,
862 15 L862P,
861 15 N861I, N861H,
86 15 L86R,