KCNH2 Variant A753S

Summary of observed carriers, functional annotations, and structural context for KCNH2 A753S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

7%

0/14 effective observations

Total carriers

4

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

A753S is present in 4 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 108% of WT with a standard error of 7%. 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 0 individuals with LQT2 and 10 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-2.818 0.55 1 0.834 18

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 – 4 1 0 –
Variant features alone – 10 10 0 –

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 A753S.
Neighbour residue Distance (Å) Observed variants
753 0 A753S,
754 4
755 5
750 6 C750X,
756 6 M756V,
749 6
757 6
841 6 V841L, V841L,
752 6 R752W, R752Q, R752P,
751 6 L751V,
726 8
845 8
758 9
774 9 D774Y, D774X,
729 9
775 9
838 9 L838R,
844 10 M844V,
722 10
730 10
837 10 D837N, D837Y, D837G,
842 10
747 10
840 10 E840Q,
748 10
773 10
725 11 Q725fsX, Q725R,
848 11
737 11 L737P,
733 11
743 11
771 11 H771fsX, H771R,
723 11 C723R, C723G, C723X,
746 11 A746S, A746X,
833 12
727 12
772 12
843 12
839 12
759 13 K759N, K759N,
728 13
817 13
852 13
770 13
777 13
736 13
724 13 L724X,
732 13
834 14 H834R,
776 14 L776I, L776P,
849 14
745 14 G745A, G745X,
846 14 P846T, P846S
818 14 S818A, S818W, S818L,
721 14 P721L,
836 14
815 14
742 14
816 14 G816V,
717 14 L717P,
831 15
832 15
781 15
731 15 H731R,
768 15