KCNH2 Variant L724P Detail

We estimate the penetrance of LQTS for KCNH2 L724P is 30%. We are unaware of any observations of this variant in individuals. L724P is not present in gnomAD. L724P 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 L724P around 30% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.683 1.0 -3 0.938 31
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.

L724P 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
724 0 L724X,
723 5 C723R, C723G, C723X,
721 5 P721L,
727 5
725 6 Q725fsX, Q725R,
720 6
726 6
696 6 R696C, R696H,
728 6
697 7 L697X,
693 7 L693X,
700 8
722 8
768 8
717 9 L717P,
767 9 D767X,
752 9 R752Q, R752P, R752W,
719 9
729 9
769 10
730 10
756 10 M756V,
699 10 E699D, E699D,
771 11 H771fsX, H771R,
766 11
716 11 V716G,
692 11
764 11
731 12 H731R,
695 12
689 12
698 12 E698X, E698K,
701 12
770 12
683 12
718 12
755 12
763 12
732 12
694 12 R694C, R694H,
690 13
680 13
704 13 A704V, A704T,
703 13
761 13
684 13
823 13 R823Q, R823T, R823W, R823fsX,
753 13 A753S,
765 14
822 14 V822M, V822L, V822L,
687 14
715 14 A715sp, A715A, A715T, A715V,
7 14
749 14
824 14
748 14
714 14
751 14 L751V,
733 14
702 14
762 14
691 15
774 15 D774X, D774Y,
821 15 D821E, D821E,
713 15 M713V,