KCNH2 Variant L693Q Detail

We estimate the penetrance of LQTS for KCNH2 L693Q is 31%. We are unaware of any observations of this variant in individuals. L693Q is not present in gnomAD. L693Q 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L693Q around 31% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.83 1.0 -2 0.958 35
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 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.

L693Q has 51 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
693 0 L693X,
692 5
696 5 R696H, R696C,
690 5
727 6
689 6
697 6 L697X,
694 6 R694H, R694C,
695 7
728 7
691 7
724 7 L724X,
731 8 H731R,
698 9 E698K, E698X,
684 9
730 10
699 10 E699D, E699D,
726 10
683 11
720 11
729 11
687 11
732 11
723 11 C723G, C723X, C723R,
700 11
725 11 Q725R, Q725fsX,
680 11
688 12
734 12 R734H, R734C,
721 12 P721L,
768 12
7 12
767 12 D767X,
752 12 R752P, R752W, R752Q,
717 12 L717P,
5 13
766 13
701 13
716 14 V716G,
733 14
681 14 R681W,
6 14 G6R,
685 14 R685C, R685H, R685P,
719 14
702 14
686 14
755 15
764 15
677 15 M677T,
756 15 M756V,
8 15