KCNH2 Variant L736V Detail

We estimate the penetrance of LQTS for KCNH2 L736V is 13%. We are unaware of any observations of this variant in individuals. L736V is not present in gnomAD. L736V 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 L736V around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.968 0.772 1 0.674 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.

L736V has 64 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
736 0
735 4 S735L,
737 5 L737P,
740 5 C740W, C740G,
733 6
781 6
743 7
831 7
739 7 H739fsX,
738 7 Q738X,
783 8 S783P,
802 8
734 8 R734H, R734C,
758 8
782 9 I782fsX, I782N,
742 9
730 10
732 10
755 10
754 10
751 10 L751V,
744 10 R744P, R744fsX, R744X, R744Q, R744G,
804 10
741 10 K741R,
830 10
803 10 D803Y, D803X,
731 11 H731R,
729 11
801 11 K801T,
760 11
829 11 D829A, D829E, D829E,
833 11
784 11 R784Q, R784G, R784W,
779 12
856 12
832 12
780 12
852 12
759 12 K759N, K759N,
745 13 G745X, G745A,
800 13
746 13 A746X, A746S,
761 13
805 13 F805C, F805S,
753 13 A753S,
750 13 C750X,
855 14 S855R, S855R, S855R,
757 14
838 14 L838R,
785 14 G785D, G785S, G785fsX,
756 14 M756V,
726 14
752 14 R752Q, R752P, R752W,
857 14 E857X,
858 14 I858V, I858T,
848 14
728 14
828 15
762 15
727 15
859 15 T859M, T859R,
748 15
687 15
799 15 L799sp,