KCNH2 Variant R734C Detail

We estimate the penetrance of LQTS for KCNH2 R734C is 18%. This variant was found in a total of 2 carriers in 0 papers or gnomAD, 0 had LQTS. R734C is present in 2 alleles in gnomAD. R734C 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 R734C around 18% (2/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.231 1.0 -3 0.93 22
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: - 2 2 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.

R734C has 42 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
734 0 R734H, R734C,
731 5 H731R,
735 5 S735L,
738 6 Q738X,
733 7
732 7
730 7
736 8
737 8 L737P,
739 8 H739fsX,
690 10
688 10
687 10
729 10
689 10
783 10 S783P,
728 11
727 11
831 11
784 11 R784Q, R784G, R784W,
740 12 C740G, C740W,
755 12
693 12 L693X,
829 12 D829E, D829E, D829A,
751 12 L751V,
760 13
726 13
743 13
758 13
802 13
692 13
686 13
781 14
744 14 R744G, R744Q, R744fsX, R744X, R744P,
691 14
752 14 R752P, R752W, R752Q,
801 14 K801T,
684 14
830 14
782 14 I782N, I782fsX,
754 14
683 14