KCNH2 Variant V822L

Summary of observed carriers, functional annotations, and structural context for KCNH2 V822L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

50%

6/14 effective observations

Total carriers

4

4 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

V822L has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 2% of WT with a standard error of 1%. 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 (%)
-2.752 0.938 1 0.869 78

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
30244407 2018 4 0 4
Literature, cohort, and gnomAD – 4 0 4 –
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 V822L.
Neighbour residue Distance (Å) Observed variants
822 0 V822M, V822L, V822L,
770 5
821 5 D821E, D821E,
823 5 R823W, R823fsX, R823T, R823Q,
769 5
789 5
768 6
820 7 G820R, G820R,
790 7
787 7
771 7 H771fsX, H771R,
824 7
788 7 E788K, E788D, E788D,
805 8 F805S, F805C,
767 9 D767X,
797 9 A797T,
780 9
766 9
799 9 L799sp,
772 9
819 10 N819K, N819K,
862 10 L862P,
818 10 S818A, S818W, S818L,
860 10
763 10
825 10
723 10 C723R, C723G, C723X,
774 10 D774Y, D774X,
796 11 V796L, V796L, V796Del,
806 11 G806R, G806R,
786 11
791 11 R791W, R791Q,
828 11
795 11 V795I,
798 11 I798fsX,
776 11 L776I, L776P,
830 11
764 12
782 12 I782fsX, I782N,
792 12
794 12 V794I, V794D,
778 12 A778T,
773 12
765 12
793 12 D793N,
800 12
12 13 N12D
761 13
826 13 T826A, T826I,
859 13 T859M, T859R,
803 13 D803Y, D803X,
804 13
832 13
752 13 R752W, R752Q, R752P,
785 13 G785S, G785fsX, G785D,
779 13
10 13
42 14 I42N,
861 14 N861H, N861I,
722 14
748 14
777 14
724 14 L724X,
807 14 E807X,
775 14
749 14
781 14
721 14 P721L,
11 14 Q11L, Q11H, Q11H,
696 14 R696C, R696H,
829 15 D829A, D829E, D829E,
762 15
858 15 I858V, I858T,
817 15
831 15