KCNH2 Variant C44S

Summary of observed carriers, functional annotations, and structural context for KCNH2 C44S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

30%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

C44S has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 61% of WT with a standard error of 11%. 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 (%)
-6.393 1.0 -2 0.974 71

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 C44S.
Neighbour residue Distance (Å) Observed variants
44 0 C44F, C44X, C44W,
43 4 Y43D, Y43C,
56 4 R56Q,
45 5 N45D, N45K, N45K,
60 6 M60T,
48 6
59 7
30 7 I30Del, I30T,
49 7 C49R, C49G,
46 7 D46Y, D46E, D46E,
29 7 F29L, F29V, F29S, F29L, F29L,
41 8 V41A,
798 8 I798fsX,
42 8 I42N,
31 8 I31S,
55 8 S55L,
47 8 G47C, G47V,
57 9 A57P,
799 9 L799sp,
800 9
859 9 T859M, T859R,
803 10 D803Y, D803X,
797 10 A797T,
19 10 I19F,
52 10 C52W,
58 10 E58K, E58D, E58D,
28 11 K28E,
54 11 Y54N, Y54X,
53 11 G53S, G53R,
32 11 A32T,
50 11 E50X,
127 11
61 11 Q61R,
801 11 K801T,
27 12 R27X, R27P,
40 12
860 12
802 12
62 12 R62Q,
51 12
129 12 F129C,
796 12 V796L, V796L, V796Del,
126 12
64 13 C64R, C64Y,
857 13 E857X,
786 13
66 13 C66R, C66G, C66Y,
15 13 L15V,
128 13 N128S,
22 13 F22Y, F22S,
804 13
23 13
787 13
68 13 F68L, F68V, F68L, F68L,
788 13 E788K, E788D, E788D,
63 13 P63H,
18 13 I18M,
789 14
858 14 I858V, I858T,
782 14 I782fsX, I782N,
785 14 G785S, G785fsX, G785D,
69 14 L69Del, L69P,
16 14 D16A,
795 14 V795I,
26 14 S26I,
124 14 M124T, M124R,
33 14 N33T
125 15
805 15 F805S, F805C,
39 15 C39R, C39X,