KCNH2 Variant V841L

Summary of observed carriers, functional annotations, and structural context for KCNH2 V841L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

13%

90% CI: 9.5% – 50.0%

3/12 effective observations

Total carriers

2

2 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

V841L has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 46% of WT with a standard error of 10%. 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 (%)
-2.754 0.967 1 0.813 85

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 2 0 2
Literature, cohort, and gnomAD – 2 0 2 –
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 V841L.
Neighbour residue Distance (Å) Observed variants
841 0 V841L, V841L,
842 4
840 6 E840Q,
838 6 L838R,
844 6 M844V,
845 6
843 6
753 6 A753S,
754 6
839 7
750 7 C750X,
757 7
837 8 D837N, D837Y, D837G,
848 8
849 9
749 9
775 10
846 10 P846T, P846S,
852 10
755 10
751 10 L751V,
836 10
756 11 M756V,
758 11
833 11
747 11
774 12 D774Y, D774X,
853 12 W853X
815 12
773 12
743 12
834 12 H834R,
835 12 R835W, R835fsX, R835Q,
817 12
809 12
752 12 R752W, R752Q, R752P,
746 12 A746S, A746X,
847 13
850 13 D850N,
779 13
816 13 G816V,
742 14
851 14
745 14 G745A, G745X,
810 14
737 14 L737P,
726 14
777 14
748 14
722 14
759 15 K759N, K759N,
776 15 L776I, L776P,
729 15
814 15
772 15