KCNH2 Variant N819K

Summary of observed carriers, functional annotations, and structural context for KCNH2 N819K. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

11%

90% CI: 1.2% – 30.1%

1/12 effective observations

Total carriers

2

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

N819K is present in 2 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 99% of WT with a standard error of 8%. 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 (%)
-3.162 0.621 0 0.529 31

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 – 2 1 0 –
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 N819K.
Neighbour residue Distance (Å) Observed variants
819 0 N819K, N819K,
820 4 G820R, G820R,
818 5 S818A, S818W, S818L,
862 5 L862P,
791 5 R791W, R791Q,
863 6 R863X, R863P
772 7
821 8 D821E, D821E,
773 8
789 8
860 8
861 8 N861H, N861I,
817 9
790 9
774 9 D774Y, D774X,
796 10 V796L, V796L, V796Del,
806 10 G806R, G806R,
770 10
822 10 V822M, V822L, V822L,
776 10 L776I, L776P,
807 10 E807X,
771 10 H771fsX, H771R,
792 10
61 10 Q61R,
816 10 G816V,
794 11 V794I, V794D,
797 11 A797T,
805 12 F805S, F805C,
775 12
795 13 V795I,
823 13 R823W, R823fsX, R823T, R823Q,
859 13 T859M, T859R,
747 13
749 13
793 13 D793N,
748 13
788 14 E788K, E788D, E788D,
60 14 M60T,
812 14 Y812S,
769 14
858 14 I858V, I858T,
808 14
40 14
36 14 V36X,
42 14 I42N,
799 14 L799sp,
778 14 A778T,
768 14
780 14
815 14
787 15
845 15
37 15