KCNH2 Variant L838R

Summary of observed carriers, functional annotations, and structural context for KCNH2 L838R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

19%

90% CI: 8.2% – 49.7%

2/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L838R has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 1% of WT with a standard error of 2%. 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 (%)
-5.254 1.0 -2 0.959 83

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
Italy Cohort 2020 1 0 1
Literature, cohort, and gnomAD – 1 0 1 –
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 L838R.
Neighbour residue Distance (Å) Observed variants
838 0 L838R,
839 5
837 6 D837N, D837Y, D837G,
841 6 V841L, V841L,
842 6
833 6
840 7 E840Q,
757 7
754 7
835 7 R835W, R835fsX, R835Q,
836 7
834 8 H834R,
809 8
779 8
758 9
852 9
843 9
853 9 W853X,
753 9 A753S,
778 10 A778T,
849 10
848 10
777 11
845 11
755 11
844 11 M844V,
832 11
750 11 C750X,
810 11
743 11
781 11
808 11
759 12 K759N, K759N,
756 12 M756V,
856 12
780 12
751 13 L751V,
807 13 E807X,
742 13
806 13 G806R, G806R,
846 13 P846T, P846S,
813 13
776 13 L776I, L776P,
831 14
749 14
804 14
850 14 D850N,
737 14 L737P,
736 14
858 14 I858V, I858T
733 14
815 14
851 14
805 15 F805S, F805C,
855 15 S855R, S855R, S855R,
746 15 A746S, A746X,
811 15
775 15