KCNH2 Variant S783P Detail

We estimate the penetrance of LQTS for KCNH2 S783P is 45%. This variant was found in a total of 3 carriers in 1 papers or gnomAD, 2 had LQTS. S783P is not present in gnomAD. S783P 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 S783P around 45% (5/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.622 0.997 -1 0.936 46
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
France Cohort 2020 3 1 2
LITERATURE, COHORT, AND GNOMAD: - 3 1 2 -
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.

S783P has 53 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
783 0 S783P,
784 4 R784Q, R784G, R784W,
782 5 I782N, I782fsX,
829 5 D829E, D829E, D829A,
801 5 K801T,
802 6
785 6 G785fsX, G785D, G785S,
735 7 S735L,
830 7
831 7
800 7
828 8
736 8
803 8 D803X, D803Y,
781 8
786 10
739 10 H739fsX,
762 10
787 10
733 10
740 10 C740G, C740W,
799 10 L799sp,
734 10 R734H, R734C,
761 10
804 11
760 11
763 11
826 11 T826A, T826I,
780 12
805 12 F805S, F805C,
732 12
737 12 L737P,
738 12 Q738X,
827 12
758 13
832 13
824 13
825 14
779 14
731 14 H731R,
764 14
759 14 K759N, K759N,
56 14 R56Q,
743 14
859 14 T859M, T859R,
798 14 I798fsX,
46 14 D46Y, D46E, D46E,
707 14
741 15 K741R,
833 15
687 15
769 15
16 15 D16A,