KCNH2 Variant P764T Detail

We estimate the penetrance of LQTS for KCNH2 P764T is 28%. We are unaware of any observations of this variant in individuals. P764T is not present in gnomAD. P764T 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 P764T around 28% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.774 0.774 -1 0.71 34
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.

P764T 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
764 0
763 3
765 4
767 5 D767X,
827 6
766 6
824 6
703 7
828 7
762 7
826 7 T826A, T826I,
700 8
699 8 E699D, E699D,
825 9
7 9
768 9
769 9
761 9
829 10 D829E, D829A, D829E,
704 10 A704V, A704T,
696 10 R696C, R696H,
830 10
823 11 R823W, R823Q, R823fsX, R823T,
787 11
481 11
786 11
6 11 G6R,
707 11
10 11
785 11 G785S, G785D, G785fsX,
479 11
721 11 P721L,
724 11 L724X,
723 12 C723X, C723R, C723G,
8 12
9 12 A9T, A9V,
822 12 V822L, V822L, V822M,
478 12 A478D,
480 12 E480V,
702 12
706 12 S706F, S706C,
697 13 L697X,
788 13 E788K, E788D, E788D,
784 13 R784W, R784G, R784Q,
695 13
701 13
760 13
720 13
4 13
13 13 T13N,
782 14 I782fsX, I782N,
770 14
698 14 E698K, E698X,
482 14 V482A,
783 14 S783P,
5 14
708 14
831 14
477 14
16 14 D16A,
780 14
719 15
693 15 L693X,
12 15 N12D,
800 15
476 15 V476I,
832 15
799 15 L799sp,