KCNH2 Variant C49S

Summary of observed carriers, functional annotations, and structural context for KCNH2 C49S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

22%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

C49S has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 116% of WT with a standard error of 17%. 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 (%)
-6.159 0.462 -2 0.917 74

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 C49S.
Neighbour residue Distance (Å) Observed variants
49 0 C49G, C49R,
48 5
53 5 G53R, G53S,
50 5 E50X,
47 5 G47C, G47V,
52 5 C52W,
46 6 D46Y, D46E, D46E,
55 6 S55L,
45 7 N45K, N45K, N45D,
44 7 C44F, C44W, C44X,
51 7
56 7 R56Q,
54 7 Y54N, Y54X,
59 8
28 9 K28E,
58 10 E58D, E58K, E58D,
101 10 K101E,
57 10 A57P,
43 10 Y43C, Y43D,
29 11 F29S, F29V, F29L, F29L, F29L,
100 11 R100G, R100Q, R100P,
30 11 I30Del, I30T,
60 11 M60T,
129 11 F129C,
27 12 R27P, R27X,
857 12 E857X
69 12 L69Del, L69P,
68 12 F68L, F68L, F68L, F68V,
859 13 T859M, T859R,
802 13
41 13 V41A,
803 13 D803X, D803Y,
102 13 D102V, D102X, D102H,
741 13 K741R,
106 13 F106L, F106L, F106L, F106V,
66 13 C66G, C66R, C66Y,
26 14 S26I,
98 14
800 14
62 14 R62Q,
31 14 I31S,
127 14
128 14 N128S,
801 14 K801T,
104 14
42 14 I42N,
798 14 I798fsX,
799 15 L799sp,
130 15 E130K,
108 15 C108Y,
23 15
19 15 I19F,