KCNH2 Variant T768R Detail

We estimate the penetrance of LQTS for KCNH2 T768R is 52%. We are unaware of any observations of this variant in individuals. T768R is not present in gnomAD. T768R has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T768R around 52% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.636 0.997 -1 0.857 58
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 5 5 -
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.

T768R has 72 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
768 0
769 5
767 5 D767X,
823 6 R823Q, R823fsX, R823W, R823T,
723 6 C723X, C723G, C723R,
771 6 H771R, H771fsX,
822 6 V822L, V822M, V822L,
770 6
766 6
821 7 D821E, D821E,
824 8
724 8 L724X,
696 8 R696H, R696C,
763 9
764 9
752 10 R752Q, R752W, R752P,
721 10 P721L,
727 10
765 10
790 10
820 10 G820R, G820R,
772 10
726 10
722 11
787 11
774 11 D774X, D774Y,
789 11
788 11 E788D, E788K, E788D,
700 12
825 12
748 12
761 12
828 12
725 12 Q725fsX, Q725R,
780 12
693 12 L693X,
7 12
749 12
699 13 E699D, E699D,
10 13
830 13
805 13 F805S, F805C,
773 13
818 13 S818A, S818L, S818W,
720 13
692 13
697 13 L697X,
826 13 T826A, T826I,
728 14
793 14 D793N,
762 14
730 14
792 14
776 14 L776I, L776P,
786 14
695 14
832 14
778 14 A778T,
12 14 N12D,
11 14 Q11L, Q11H, Q11H,
819 14 N819K, N819K,
797 14 A797T,
827 14
799 15 L799sp,
703 15
775 15
791 15 R791W, R791Q,
8 15
756 15 M756V,
862 15 L862P,
751 15 L751V,
753 15 A753S,