KCNH2 Variant T826A Detail

We estimate the penetrance of LQTS for KCNH2 T826A is 27%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 0 had LQTS. T826A is not present in gnomAD. T826A 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 T826A around 27% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.947 0.995 0 0.951 39
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
Japan Cohort 2020 1 1 0
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.

T826A has 60 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
826 0 T826A, T826I,
825 4
828 5
827 5
786 5
785 6 G785D, G785fsX, G785S,
765 6
824 6
764 7
763 7
16 8 D16A,
787 8
829 9 D829A, D829E, D829E,
13 9 T13N,
479 9
766 9
784 9 R784G, R784W, R784Q,
10 9
788 10 E788D, E788K, E788D,
767 10 D767X,
800 10
9 10 A9T, A9V,
762 10
480 10 E480V,
20 10 R20L, R20G,
830 11
801 11 K801T,
783 11 S783P,
481 11
782 11 I782fsX, I782N,
17 11
799 11 L799sp,
15 11 L15V,
823 11 R823Q, R823fsX, R823W, R823T,
12 11 N12D,
798 12 I798fsX,
7 12
478 12 A478D,
703 12
19 12 I19F,
8 12
822 13 V822L, V822M, V822L,
769 13
14 13
761 13
477 13
768 13
482 13 V482A,
11 13 Q11L, Q11H, Q11H,
6 14 G6R,
797 14 A797T,
699 14 E699D, E699D,
803 14 D803Y, D803X,
789 14
18 14 I18M,
707 14
43 15 Y43C, Y43D,
700 15
831 15
802 15