KCNH2 Variant I728L Detail

We estimate the penetrance of LQTS for KCNH2 I728L is 28%. We are unaware of any observations of this variant in individuals. I728L is not present in gnomAD. I728L 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 I728L around 28% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.922 0.55 1 0.812 40
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.

I728L 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
728 0
729 4
727 5
726 5
732 6
731 6 H731R,
725 6 Q725fsX, Q725R,
724 6 L724X,
730 7
693 7 L693X,
717 7 L717P,
689 8
687 8
683 8
720 8
697 8 L697X,
756 9 M756V,
755 9
733 9
752 9 R752Q, R752P, R752W,
696 10 R696C, R696H,
723 10 C723R, C723G, C723X,
716 10 V716G,
721 10 P721L,
690 10
684 10
713 11 M713V,
734 11 R734H, R734C,
722 11
714 11
692 11
719 11
694 11 R694C, R694H,
680 12
686 12
688 12
760 12
718 12
758 12
715 12 A715sp, A715A, A715T, A715V,
700 12
753 13 A753S,
751 13 L751V,
759 13 K759N, K759N,
698 13 E698X, E698K,
737 13 L737P,
754 13
695 13
691 13
768 14
757 14
735 14 S735L,
831 14
699 14 E699D, E699D,
701 14
736 14
771 15 H771fsX, H771R,
749 15
748 15
738 15 Q738X,
767 15 D767X,
711 15 I711V,