KCNH2 Variant C750G Detail

We estimate the penetrance of LQTS for KCNH2 C750G is 28%. We are unaware of any observations of this variant in individuals. C750G is not present in gnomAD. C750G 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 C750G around 28% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-11.656 0.999 -3 0.913 29
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.

C750G has 60 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
750 0 C750X,
749 3
747 5
751 5 L751V,
845 5
753 6 A753S,
746 6 A746S, A746X,
754 6
848 6
841 7 V841L, V841L,
748 7
773 7
752 8 R752Q, R752W, R752P,
774 8 D774X, D774Y,
842 9
743 9
745 9 G745X, G745A,
844 9 M844V,
772 9
755 9
775 10
737 10 L737P,
846 10 P846T, P846S,
817 10
852 10
847 10
849 10
771 11 H771R, H771fsX,
838 11 L838R,
757 11
730 11
756 11 M756V,
742 11
851 11
726 11
843 12
818 12 S818A, S818L, S818W,
758 12
840 13 E840Q,
744 13 R744Q, R744X, R744P, R744G, R744fsX,
729 13
733 13
839 13
816 13 G816V,
736 13
770 14
850 14 D850N,
837 14 D837G, D837N, D837Y,
853 14 W853X,
727 14
776 14 L776I, L776P,
815 14
738 14 Q738X,
722 14
820 14 G820R, G820R,
723 14 C723X, C723G, C723R,
740 14 C740G, C740W,
821 14 D821E, D821E,
833 15
855 15 S855R, S855R, S855R,