KCNH2 Variant N819K Detail

We estimate the penetrance of LQTS for KCNH2 N819K is 21%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. N819K is present in 1 alleles in gnomAD. N819K has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 N819K around 21% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.162 0.621 0 0.529 31
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT2 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 1 1 0 -
VARIANT FEATURES ALONE: - 10 8 2 -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

N819K has 53 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: 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 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
819 0 N819K, N819K,
820 4 G820R, G820R,
818 5 S818L, S818A, S818W,
862 5 L862P,
791 5 R791Q, R791W,
863 6 R863P, R863X,
772 7
821 8 D821E, D821E,
773 8
789 8
860 8
861 8 N861H, N861I,
817 9
790 9
774 9 D774X, D774Y,
796 10 V796Del, V796L, V796L,
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 F805C, F805S,
775 12
795 13 V795I,
823 13 R823Q, R823T, R823W, R823fsX,
859 13 T859R, T859M,
747 13
749 13
793 13 D793N,
748 13
788 14 E788D, E788K, 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