KCNH2 Variant L730Q Detail

We estimate the penetrance of LQTS for KCNH2 L730Q is 26%. We are unaware of any observations of this variant in individuals. L730Q is not present in gnomAD. L730Q 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 L730Q around 26% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.838 0.969 -2 0.897 30
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.

L730Q 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
730 0
727 5
729 5
726 6
731 6 H731R,
733 6
752 6 R752Q, R752P, R752W,
755 7
751 7 L751V,
728 7
732 7
737 7 L737P,
734 7 R734H, R734C,
738 9 Q738X,
748 9
756 9 M756V,
754 9
735 10 S735L,
736 10
693 10 L693X,
753 10 A753S,
758 10
749 10
724 10 L724X,
725 10 Q725R, Q725fsX,
690 11
743 11
750 11 C750X,
723 11 C723X, C723R, C723G,
689 11
687 12
692 12
696 12 R696C, R696H,
771 12 H771fsX, H771R,
831 12
739 13 H739fsX,
747 13
746 13 A746X, A746S,
757 13
717 13 L717P,
722 13
760 13
740 13 C740W, C740G,
768 14
759 14 K759N, K759N,
697 14 L697X,
744 14 R744P, R744fsX, R744X, R744Q, R744G,
721 14 P721L,
688 14
683 14
720 14
774 14 D774X, D774Y,
781 15
772 15
745 15 G745X, G745A,
691 15