KCNH2 Variant K757Q Detail

We estimate the penetrance of LQTS for KCNH2 K757Q is 42%. We are unaware of any observations of this variant in individuals. K757Q is not present in gnomAD. K757Q 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 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K757Q around 42% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.941 0.983 1 0.849 54
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 6 4 -
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.

K757Q has 54 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
757 0
837 5 D837G, D837N, D837Y,
756 6 M756V,
754 6
753 6 A753S,
758 6
755 6
838 7 L838R,
833 7
841 7 V841L, V841L,
840 8 E840Q,
834 8 H834R,
759 8 K759N, K759N,
836 9
729 10
832 10
839 10
726 11
842 11
750 11 C750X,
733 11
725 11 Q725fsX, Q725R,
751 11 L751V,
752 11 R752Q, R752W, R752P,
722 12
779 12
749 12
835 12 R835W, R835fsX, R835Q,
844 12 M844V,
845 12
778 12 A778T,
760 12
831 12
843 13
730 13
714 13
777 13
775 13
781 13
717 13 L717P,
732 13
743 13
737 13 L737P,
728 14
736 14
780 14
848 14
852 14
774 14 D774X, D774Y,
718 15
761 15
723 15 C723X, C723G, C723R,
809 15
727 15