KCNH2 Variant S818W

Summary of observed carriers, functional annotations, and structural context for KCNH2 S818W. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

38%

90% CI: 17.3% – 61.7%

4/12 effective observations

Total carriers

2

2 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

S818W 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 4%. 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 (%)
-6.196 1.0 -3 0.955 57

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
26496715 2015 1 0 1
30036649 2018 1 0 1
Literature, cohort, and gnomAD – 2 0 2 –
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 S818W.
Neighbour residue Distance (Å) Observed variants
818 0 S818A, S818W, S818L,
773 4
819 5 N819K, N819K,
817 5
772 5
820 5 G820R, G820R,
774 5 D774Y, D774X,
862 6 L862P,
776 6 L776I, L776P,
816 7 G816V,
863 7 R863X, R863P
775 8
770 8
821 8 D821E, D821E,
771 8 H771fsX, H771R,
807 9 E807X,
806 9 G806R, G806R,
749 10
861 10 N861H, N861I,
791 10 R791W, R791Q,
822 10 V822M, V822L, V822L,
815 10
845 11
747 11
860 11
789 11
777 11
778 11 A778T,
805 11 F805S, F805C,
790 12
748 12
750 12 C750X,
812 12 Y812S,
844 12 M844V,
769 12
780 13
808 13
752 13 R752W, R752Q, R752P,
768 13
792 13
779 14
835 14 R835W, R835fsX, R835Q,
796 14 V796L, V796L, V796Del,
823 14 R823W, R823fsX, R823T, R823Q,
847 14
753 14 A753S,
814 14
846 14 P846T, P846S,
858 14 I858V, I858T,
723 14 C723R, C723G, C723X,
797 14 A797T,
746 15 A746S, A746X,
61 15 Q61R,
751 15 L751V,
809 15
859 15 T859M, T859R,
794 15 V794I, V794D,