KCNH2 Variant R752G Detail

We estimate the penetrance of LQTS for KCNH2 R752G is 21%. We are unaware of any observations of this variant in individuals. R752G is not present in gnomAD. R752G 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 R752G around 21% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.709 1.0 -3 0.894 21
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.

R752G has 58 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
752 0 R752P, R752W, R752Q,
726 4
749 5
751 6 L751V,
753 6 A753S,
730 6
748 7
771 7 H771R, H771fsX,
727 7
723 7 C723G, C723X, C723R,
755 7
756 8 M756V,
750 8 C750X,
729 8
774 8 D774Y, D774X,
754 9
722 9
724 9 L724X,
725 9 Q725R, Q725fsX,
772 9
728 9
747 9
768 10
770 10
773 10
737 11 L737P,
733 11
721 11 P721L,
775 11
821 11 D821E, D821E,
757 11
746 12 A746S, A746X,
769 12
845 12
731 12 H731R,
758 12
732 12
841 12 V841L, V841L,
696 12 R696H, R696C,
693 12 L693X,
818 13 S818W, S818A, S818L,
743 13
820 13 G820R, G820R,
822 13 V822L, V822M, V822L,
717 14 L717P,
767 14 D767X,
738 14 Q738X,
720 14
823 14 R823T, R823Q, R823fsX, R823W,
776 14 L776P, L776I,
734 14 R734H, R734C,
848 14
817 14
844 14 M844V,
736 14
777 14
745 15 G745X, G745A,
692 15