KCNH2 Variant A34S

Summary of observed carriers, functional annotations, and structural context for KCNH2 A34S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

11%

1/11 effective observations

Total carriers

1

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

A34S is present in 1 alleles 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 20%. 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 (%)
-1.857 0.994 0 0.915 66

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 – 1 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 A34S.
Neighbour residue Distance (Å) Observed variants
34 0 A34T,
35 4 R35W,
33 4 N33T
36 5 V36X,
39 6 C39R, C39X,
123 6
122 6
124 6 M124T, M124R,
32 7 A32T,
125 7
40 8
37 9
86 9 L86R,
38 9
794 9 V794I, V794D,
121 9 A121fsX,
795 9 V795I,
87 10 L87P,
64 10 C64R, C64Y,
115 11 V115M,
42 11 I42N,
31 11 I31S,
796 11 V796L, V796L, V796Del,
114 11 P114S,
41 11 V41A,
116 12 K116Q,
89 12 A89G, A89V,
63 12 P63H,
126 12
88 12
117 12
85 12 A85P, A85V,
120 13
793 13 D793N,
792 13
83 13 A83P, A83fsX,
65 13 T65P,
791 13 R791W, R791Q,
127 13
797 14 A797T,
15 14 L15V,
12 14 N12D,
30 14 I30Del, I30T,
113 14 V113Del,
14 14
112 14 V112M,
790 14
90 14 E90K,
61 14 Q61R,
119 15 D119H, D119G,
798 15 I798fsX,