KCNH2 Variant T859R Detail

We estimate the penetrance of LQTS for KCNH2 T859R is 21%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. T859R is present in 1 alleles in gnomAD. T859R 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 T859R around 21% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None 0.249 29
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.

T859R has 68 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
859 0 T859M, T859R,
858 5 I858V, I858T,
860 5
804 5
57 5 A57P,
56 6 R56Q,
803 6 D803X, D803Y,
60 7 M60T,
799 7 L799sp,
805 7 F805S, F805C,
857 7 E857X,
861 8 N861I, N861H,
806 8 G806R, G806R,
55 9 S55L,
61 9 Q61R,
797 9 A797T,
44 9 C44W, C44X, C44F,
800 9
862 10 L862P,
59 10
856 10
58 10 E58D, E58K, E58D,
782 10 I782N, I782fsX,
789 10
798 10 I798fsX,
781 10
802 10
787 11
42 11 I42N,
779 11
807 11 E807X,
43 11 Y43C, Y43D,
808 11
796 11 V796L, V796Del, V796L,
780 11
41 11 V41A,
62 12 R62Q,
741 13 K741R,
801 13 K801T,
49 13 C49R, C49G,
788 13 E788D, E788K, E788D,
822 13 V822L, V822M, V822L,
819 13 N819K, N819K,
855 13 S855R, S855R, S855R,
740 13 C740G, C740W,
46 13 D46Y, D46E, D46E,
786 13
45 14 N45K, N45K, N45D,
820 14 G820R, G820R,
40 14
54 14 Y54N, Y54X,
778 14 A778T,
783 14 S783P,
853 14 W853X,
776 14 L776P, L776I,
742 14
785 14 G785fsX, G785D, G785S,
830 14
790 14
854 15
31 15 I31S,
48 15
852 15
818 15 S818W, S818A, S818L,
795 15 V795I,
770 15
53 15 G53R, G53S,
736 15