KCNH2 Variant K741E Detail

We estimate the penetrance of LQTS for KCNH2 K741E is 15%. We are unaware of any observations of this variant in individuals. K741E is not present in gnomAD. K741E 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 K741E around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.857 0.249 1 0.727 21
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.

K741E has 40 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
741 0 K741R,
742 5
740 5 C740W, C740G,
855 6 S855R, S855R, S855R,
744 6 R744P, R744fsX, R744X, R744Q, R744G,
856 7
857 7 E857X,
743 8
739 9 H739fsX,
802 9
745 10 G745X, G745A,
851 10
854 10
852 10
736 10
804 10
737 11 L737P,
55 11 S55L,
803 11 D803Y, D803X,
738 11 Q738X,
858 12 I858V, I858T,
781 12
56 12 R56Q,
746 12 A746X, A746S,
735 12 S735L,
853 13 W853X,
859 13 T859M, T859R,
46 13 D46E, D46Y, D46E,
848 13
49 13 C49R, C49G,
57 13 A57P,
53 14 G53S, G53R,
782 14 I782fsX, I782N,
801 14 K801T,
58 14 E58D, E58D, E58K,
50 14 E50X,
783 15 S783P,
751 15 L751V,
800 15
849 15