KCNH2 Variant G749S Detail

We estimate the penetrance of LQTS for KCNH2 G749S is 25%. We are unaware of any observations of this variant in individuals. G749S is not present in gnomAD. G749S 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 G749S around 25% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.534 0.887 0 0.836 33
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.

G749S has 61 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
749 0
750 3 C750X,
747 5
751 5 L751V,
752 5 R752Q, R752P, R752W,
774 5 D774X, D774Y,
748 6
773 6
753 6 A753S,
772 7
845 7
771 7 H771fsX, H771R,
746 8 A746S, A746X,
754 8
775 8
841 9 V841L, V841L,
726 9
755 10
817 10
818 10 S818W, S818A, S818L,
848 10
770 10
844 10 M844V,
730 10
756 11 M756V,
821 11 D821E, D821E,
723 11 C723X, C723R, C723G,
737 11 L737P,
745 11 G745X, G745A,
820 11 G820R, G820R,
743 11
842 12
722 12
776 12 L776I, L776P,
727 12
757 12
729 12
816 12 G816V,
768 12
846 13 P846S, P846T,
847 13
819 13 N819K, N819K,
758 13
777 13
725 14 Q725fsX, Q725R,
838 14 L838R,
769 14
815 14
733 14
849 14
843 14
852 14
840 14 E840Q,
822 14 V822L, V822L, V822M,
724 14 L724X,
742 14
851 14
728 15
738 15 Q738X,
744 15 R744Q, R744X, R744G, R744fsX, R744P,
862 15 L862P,