KCNH2 Variant A40S

Summary of observed carriers, functional annotations, and structural context for KCNH2 A40S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

17%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

A40S has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 125% of WT with a standard error of 13%. 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 (%)
-1.449 0.155 0 0.72 52

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 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 A40S.
Neighbour residue Distance (Å) Observed variants
40 0
41 4 V41A,
39 4 C39X, C39R,
32 5 A32T,
33 6 N33T,
63 6 P63H,
42 6 I42N,
36 6 V36X,
61 7 Q61R,
64 7 C64R, C64Y,
796 7 V796L, V796L, V796Del,
38 7
60 8 M60T,
62 8 R62Q,
34 8 A34T,
31 8 I31S,
37 9
795 9 V795I,
797 9 A797T,
35 9 R35W,
125 9
59 9
30 10 I30T, I30Del,
124 10 M124T, M124R,
65 10 T65P,
794 10 V794D, V794I,
66 10 C66R, C66G, C66Y,
798 11 I798fsX,
791 11 R791Q, R791W,
43 11 Y43C, Y43D,
860 12
44 12 C44X, C44W, C44F,
127 12
86 12 L86R,
789 12
123 12
57 13 A57P,
126 13
790 13
67 13
68 13 F68L, F68L, F68V, F68L,
56 13 R56Q,
788 13 E788K, E788D, E788D,
122 14
58 14 E58D, E58D, E58K,
859 14 T859R, T859M,
15 14 L15V,
29 14 F29V, F29L, F29S, F29L, F29L,
799 14 L799sp,
819 14 N819K, N819K,
83 14 A83P, A83fsX,
48 14
792 14
87 15 L87P,
82 15 I82Ins, I82dup, I82T, I82Del,
114 15 P114S,