KCNH2 Variant P765R Detail

We estimate the penetrance of LQTS for KCNH2 P765R is 31%. We are unaware of any observations of this variant in individuals. P765R is not present in gnomAD. P765R 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P765R around 31% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.746 1.0 -2 0.842 35
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 7 3 -
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.

P765R 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
765 0
764 4
766 4
824 5
767 6 D767X,
827 6
826 6 T826A, T826I,
825 6
7 6
763 7
10 7
828 8
9 8 A9T, A9V,
8 8
481 8
699 8 E699D, E699D,
6 9 G6R,
703 9
823 9 R823Q, R823fsX, R823W, R823T,
480 10 E480V,
786 10
13 10 T13N,
479 10
768 10
696 10 R696H, R696C,
762 10
787 10
700 11
482 11 V482A,
785 11 G785D, G785fsX, G785S,
788 11 E788D, E788K, E788D,
478 11 A478D,
769 11
829 12 D829A, D829E, D829E,
12 12 N12D,
11 12 Q11L, Q11H, Q11H,
16 12 D16A,
822 12 V822L, V822M, V822L,
695 12
830 13
5 13
477 13
704 13 A704T, A704V,
761 13
4 13
702 13
476 13 V476I,
724 14 L724X,
723 14 C723X, C723G, C723R,
707 14
784 14 R784G, R784W, R784Q,
706 14 S706C, S706F,
697 14 L697X,
15 14 L15V,
698 14 E698X, E698K,
483 14 V483I,
721 15 P721L,
14 15
790 15
800 15
17 15
799 15 L799sp,
782 15 I782fsX, I782N,
770 15
789 15