KCNH2 Variant L751R Detail

We estimate the penetrance of LQTS for KCNH2 L751R is 13%. We are unaware of any observations of this variant in individuals. L751R is not present in gnomAD. L751R 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L751R around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.836 1.0 -2 0.959 9
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.

L751R has 62 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
751 0 L751V,
750 5 C750X,
749 5
754 6
737 6 L737P,
748 6
752 6 R752P, R752W, R752Q,
753 6 A753S,
747 6
746 7 A746S, A746X,
730 7
755 7
743 7
726 9
745 9 G745X, G745A,
733 9
848 9
845 10
729 10
738 10 Q738X,
736 10
756 10 M756V,
758 10
841 10 V841L, V841L,
742 11
727 11
773 11
774 11 D774Y, D774X,
744 11 R744G, R744Q, R744fsX, R744X, R744P,
771 11 H771R, H771fsX,
772 11
757 11
740 12 C740G, C740W,
852 12
735 12 S735L,
842 12
734 12 R734H, R734C,
732 12
731 13 H731R,
838 13 L838R,
728 13
851 13
723 13 C723G, C723X, C723R,
739 13 H739fsX,
775 13
844 13 M844V,
725 14 Q725R, Q725fsX,
849 14
781 14
722 14
833 14
831 14
847 14
817 14
724 14 L724X,
770 14
741 15 K741R,
846 15 P846S, P846T,
818 15 S818W, S818A, S818L,
821 15 D821E, D821E,
837 15 D837N, D837G, D837Y,
768 15