KCNH2 Variant A746D Detail

We estimate the penetrance of LQTS for KCNH2 A746D is 10%. We are unaware of any observations of this variant in individuals. A746D is not present in gnomAD. A746D has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A746D around 10% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.094 0.983 -1 0.904 5
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 10 0 -
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.

A746D has 44 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
746 0 A746S, A746X,
745 3 G745A, G745X,
747 4
750 6 C750X,
848 6
751 7 L751V,
748 7
743 7
749 8
851 8
744 8 R744X, R744Q, R744fsX, R744P, R744G,
742 8
737 9 L737P,
845 9
847 10
852 10
754 10
773 11
849 11
772 11
753 11 A753S,
752 12 R752Q, R752P, R752W,
738 12 Q738X,
740 12 C740W, C740G,
846 12 P846S, P846T,
855 12 S855R, S855R, S855R,
842 12
741 12 K741R,
841 12 V841L, V841L,
774 12 D774X, D774Y,
850 13 D850N,
730 13
736 13
755 13
817 13
771 14 H771fsX, H771R,
856 14
739 14 H739fsX,
854 14
853 14 W853X,
844 14 M844V,
818 15 S818L, S818A, S818W,
733 15
838 15 L838R,