KCNH2 Variant T761I Detail

We estimate the penetrance of LQTS for KCNH2 T761I is 21%. We are unaware of any observations of this variant in individuals. T761I is not present in gnomAD. T761I 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 T761I around 21% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.594 0.786 -1 0.824 25
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: - 0 0 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.

T761I has 65 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
761 0
830 4
760 5
762 5
832 6
831 6
763 7
759 7 K759N, K759N,
829 8 D829A, D829E, D829E,
780 8
769 8
828 9
764 9
721 10 P721L,
782 10 I782fsX, I782N,
707 10
758 10
833 10
767 10 D767X,
781 10
783 10 S783P,
700 11
723 11 C723X, C723G, C723R,
704 11 A704T, A704V,
778 11 A778T,
703 11
722 11
733 12
805 12 F805S, F805C,
824 12
787 12
732 12
784 12 R784G, R784W, R784Q,
834 12 H834R,
768 12
779 12
827 12
770 12
713 12 M713V,
822 13 V822L, V822M, V822L,
719 13
785 13 G785D, G785fsX, G785S,
708 13
826 13 T826A, T826I,
765 13
736 13
714 13
724 13 L724X,
720 13
766 13
735 13 S735L,
686 13
687 13
777 14
786 14
729 14
755 14
804 14
803 14 D803Y, D803X,
800 14
725 15 Q725fsX, Q725R,
757 15
799 15 L799sp,
706 15 S706C, S706F,
825 15