KCNH2 Variant A753P Detail

We estimate the penetrance of LQTS for KCNH2 A753P is 16%. We are unaware of any observations of this variant in individuals. A753P is not present in gnomAD. A753P 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A753P around 16% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.73 0.999 -1 0.945 18
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 9 1 -
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.

A753P has 65 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
753 0 A753S,
754 4
755 5
750 6 C750X,
756 6 M756V,
749 6
757 6
841 6 V841L, V841L,
752 6 R752Q, R752W, R752P,
751 6 L751V,
726 8
845 8
758 9
774 9 D774X, D774Y,
729 9
775 9
838 9 L838R,
844 10 M844V,
722 10
730 10
837 10 D837G, D837N, D837Y,
842 10
747 10
840 10 E840Q,
748 10
773 10
725 11 Q725fsX, Q725R,
848 11
737 11 L737P,
733 11
743 11
771 11 H771R, H771fsX,
723 11 C723X, C723G, C723R,
746 11 A746S, A746X,
833 12
727 12
772 12
843 12
839 12
759 13 K759N, K759N,
728 13
817 13
852 13
770 13
777 13
736 13
724 13 L724X,
732 13
834 14 H834R,
776 14 L776I, L776P,
849 14
745 14 G745X, G745A,
846 14 P846T, P846S,
818 14 S818A, S818L, S818W,
721 14 P721L,
836 14
815 14
742 14
816 14 G816V,
717 14 L717P,
831 15
832 15
781 15
731 15 H731R,
768 15