KCNH2 Variant Y43S

Summary of observed carriers, functional annotations, and structural context for KCNH2 Y43S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

32%

90% CI: 11.4% – 57.6%

3/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

Y43S 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 12%. 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 3 individuals with LQT2 and 7 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-5.357 0.021 -3 0.838 67

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 7 3 –

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 Y43S.
Neighbour residue Distance (Å) Observed variants
43 0 Y43D, Y43C,
44 4 C44F, C44X, C44W,
798 5 I798fsX,
31 6 I31S,
45 6 N45D, N45K, N45K,
29 6 F29L, F29V, F29S, F29L, F29L,
42 6 I42N,
30 6 I30Del, I30T,
19 7 I19F,
56 7 R56Q,
799 8 L799sp,
41 8 V41A,
800 8
60 8 M60T,
797 8 A797T,
15 9 L15V,
46 9 D46Y, D46E, D46E,
48 9
32 9 A32T,
59 10
18 10 I18M,
786 10
16 10 D16A,
126 10
47 10 G47C, G47V,
788 10 E788K, E788D, E788D,
803 10 D803Y, D803X,
49 10 C49R, C49G,
22 10 F22Y, F22S,
127 11
796 11 V796L, V796L, V796Del,
801 11 K801T,
27 11 R27X, R27P,
23 11
787 11
859 11 T859M, T859R,
40 11
124 11 M124T, M124R,
795 11 V795I,
785 11 G785S, G785fsX, G785D,
28 12 K28E,
55 12 S55L,
789 12
57 12 A57P,
128 12 N128S,
17 12
860 12
33 12 N33T
802 12
61 13 Q61R,
129 13 F129C,
14 13
20 13 R20G, R20L,
125 13
825 13
64 13 C64R, C64Y,
782 13 I782fsX, I782N,
21 13
12 13 N12D,
26 14 S26I,
50 14 E50X,
52 14 C52W,
62 14 R62Q,
13 14 T13N,
58 14 E58K, E58D, E58D,
804 14
25 14 Q25P,
24 14
39 14 C39R, C39X,
51 15
63 15 P63H,
826 15 T826A, T826I,
113 15 V113Del,
66 15 C66R, C66G, C66Y,
115 15 V115M,
54 15 Y54N, Y54X,
53 15 G53S, G53R,
805 15 F805S, F805C,
790 15
824 15