KCNH2 Variant G773A Detail

We estimate the penetrance of LQTS for KCNH2 G773A is 53%. We are unaware of any observations of this variant in individuals. G773A is not present in gnomAD. G773A 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G773A around 53% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.836 1.0 0 0.975 62
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 5 5 -
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.

G773A has 57 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
773 0
774 3 D774Y, D774X,
772 4
818 4 S818W, S818A, S818L,
817 5
749 6
775 7
747 7
771 7 H771R, H771fsX,
845 7
820 7 G820R, G820R,
750 7 C750X,
819 8 N819K, N819K,
816 8 G816V,
748 8
776 8 L776P, L776I,
770 9
821 9 D821E, D821E,
863 10 R863P, R863X,
844 10 M844V,
862 10 L862P,
752 10 R752P, R752W, R752Q,
753 10 A753S,
746 11 A746S, A746X,
751 11 L751V,
815 11
847 11
846 12 P846S, P846T,
791 12 R791W, R791Q,
848 12
777 12
841 12 V841L, V841L,
822 12 V822L, V822M, V822L,
807 12 E807X,
806 13 G806R, G806R,
754 13
769 13
768 13
778 13 A778T,
723 13 C723G, C723X, C723R,
790 13
842 13
792 14
745 14 G745X, G745A,
789 14
861 14 N861I, N861H,
726 14
722 14
843 14
812 14 Y812S,
814 15
823 15 R823T, R823Q, R823fsX, R823W,
805 15 F805S, F805C,
755 15
849 15
756 15 M756V,
860 15