KCNH2 Variant A772D Detail

We estimate the penetrance of LQTS for KCNH2 A772D is 48%. We are unaware of any observations of this variant in individuals. A772D is not present in gnomAD. A772D 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 A772D around 48% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.241 0.941 -2 0.645 51
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.

A772D has 56 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
772 0
773 4
774 5 D774X, D774Y,
820 5 G820R, G820R,
771 5 H771R, H771fsX,
818 5 S818A, S818L, S818W,
821 6 D821E, D821E,
749 7
748 7
819 7 N819K, N819K,
770 7
747 8
817 8
791 9 R791W, R791Q,
752 9 R752Q, R752W, R752P,
750 9 C750X,
822 9 V822L, V822M, V822L,
775 10
862 10 L862P,
790 10
776 10 L776I, L776P,
792 10
768 10
845 11
863 11 R863X, R863P,
751 11 L751V,
816 11 G816V,
789 11
746 11 A746S, A746X,
823 11 R823Q, R823fsX, R823W, R823T,
769 11
753 12 A753S,
723 12 C723X, C723G, C723R,
793 13 D793N,
806 13 G806R, G806R,
794 13 V794D, V794I,
844 13 M844V,
726 13
807 14 E807X,
777 14
860 14
847 14
805 14 F805S, F805C,
778 14 A778T,
815 14
796 14 V796L, V796Del, V796L,
861 14 N861I, N861H,
848 14
722 14
745 14 G745X, G745A,
727 15
754 15
730 15
780 15
841 15 V841L, V841L,
846 15 P846T, P846S,