KCNH2 Variant P692A Detail

We estimate the penetrance of LQTS for KCNH2 P692A is 25%. We are unaware of any observations of this variant in individuals. P692A is not present in gnomAD. P692A 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 P692A around 25% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.781 0.805 -1 0.688 31
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.

P692A has 35 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
692 0
691 5
693 5 L693X,
690 5
695 6
696 7 R696C, R696H,
694 7 R694C, R694H,
689 8
727 9
697 10 L697X,
731 10 H731R,
698 11 E698K, E698X,
7 11
699 11 E699D, E699D,
724 11 L724X,
728 11
5 11
684 12
730 12
766 12
8 12
734 13 R734C, R734H,
688 13
6 13 G6R,
767 13 D767X,
768 13
726 13
403 14
723 14 C723X, C723R, C723G,
732 14
687 14
700 14
729 15
752 15 R752Q, R752P, R752W,
683 15