KCNH2 Variant P742R Detail

We estimate the penetrance of LQTS for KCNH2 P742R is 39%. We are unaware of any observations of this variant in individuals. P742R is not present in gnomAD. P742R has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P742R around 39% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.507 0.813 -2 0.787 43
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 7 3 -
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.

P742R has 52 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
742 0
743 4
741 5 K741R,
855 5 S855R, S855R, S855R,
852 6
740 6 C740G, C740W,
856 6
744 6 R744G, R744Q, R744fsX, R744X, R744P,
745 6 G745X, G745A,
851 7
848 8
737 8 L737P,
746 8 A746S, A746X,
854 9
857 9 E857X,
853 9 W853X,
736 9
781 10
739 10 H739fsX,
751 11 L751V,
849 11
804 11
738 11 Q738X,
754 11
750 11 C750X,
858 12 I858V, I858T,
850 12 D850N,
802 12
747 12
735 12 S735L,
842 12
779 13
838 13 L838R,
803 13 D803X, D803Y,
758 13
733 14
841 14 V841L, V841L,
845 14
847 14
859 14 T859M, T859R,
755 14
749 14
833 14
753 14 A753S,
808 14
831 14
748 14
782 14 I782N, I782fsX,
809 15
55 15 S55L,
846 15 P846S, P846T,
810 15