KCNH2 Variant C723S Detail

We estimate the penetrance of LQTS for KCNH2 C723S is 13%. We are unaware of any observations of this variant in individuals. C723S is not present in gnomAD. C723S 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 C723S around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.407 0.119 -1 0.755 12
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 9 1 -
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.

C723S has 64 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
723 0 C723X, C723R, C723G,
724 5 L724X,
721 5 P721L,
722 5
768 6
726 6
769 6
725 7 Q725R, Q725fsX,
752 7 R752Q, R752P, R752W,
771 7 H771fsX, H771R,
727 8
770 8
767 8 D767X,
696 9 R696C, R696H,
720 9
728 10
756 10 M756V,
700 10
774 10 D774X, D774Y,
822 10 V822M, V822L, V822L,
729 11
766 11
749 11
719 11
763 11
730 11
717 11 L717P,
693 11 L693X,
753 11 A753S,
761 11
821 11 D821E, D821E,
823 11 R823W, R823fsX, R823Q, R823T,
697 11 L697X,
764 12
755 12
772 12
748 12
832 12
780 13
824 13
777 13
775 13
778 13 A778T,
751 13 L751V,
773 13
776 13 L776I, L776P,
699 13 E699D, E699D,
820 13 G820R, G820R,
718 14
830 14
765 14
762 14
750 14 C750X,
692 14
818 14 S818W, S818L, S818A,
731 14 H731R,
754 14
716 15 V716G,
834 15 H834R,
757 15
759 15 K759N, K759N,
703 15
704 15 A704T, A704V,
805 15 F805C, F805S,