KCNH2 Variant R696P Detail

We estimate the penetrance of LQTS for KCNH2 R696P is 42%. We are unaware of any observations of this variant in individuals. R696P is not present in gnomAD. R696P 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 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R696P around 42% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.679 1.0 -2 0.955 46
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 6 4 -
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.

R696P has 58 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
696 0 R696C, R696H,
693 5 L693X,
724 6 L724X,
695 6
697 6 L697X,
699 7 E699D, E699D,
692 7
727 7
767 7 D767X,
766 8
700 8
768 8
7 9
698 9 E698X, E698K,
723 9 C723X, C723R, C723G,
694 9 R694H, R694C,
728 10
764 10
690 10
691 10
720 10
721 10 P721L,
765 10
689 11
726 11
6 11 G6R,
5 11
725 12 Q725R, Q725fsX,
823 12 R823W, R823fsX, R823Q, R823T,
8 12
703 12
701 12
769 12
763 12
731 12 H731R,
752 12 R752Q, R752P, R752W,
730 12
824 12
702 13
684 13
771 13 H771fsX, H771R,
729 13
680 13
10 13
719 14
704 14 A704T, A704V,
722 14
717 14 L717P,
683 14
9 14 A9T, A9V,
481 14
770 14
822 14 V822M, V822L, V822L,
4 15
821 15 D821E, D821E,
827 15
732 15
716 15 V716G,