KCNH2 Variant Q695E Detail

We estimate the penetrance of LQTS for KCNH2 Q695E is 12%. We are unaware of any observations of this variant in individuals. Q695E is not present in gnomAD. Q695E 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 Q695E around 12% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.917 0.243 2 0.657 18
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.

Q695E has 45 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
695 0
692 6
694 6 R694H, R694C,
696 6 R696H, R696C,
5 6
691 6
699 6 E699D, E699D,
698 6 E698X, E698K,
693 7 L693X,
7 7
697 8 L697X,
6 8 G6R,
690 9
8 10
403 10
689 10
766 11
702 11
700 11
724 12 L724X,
684 12
4 12
727 12
767 12 D767X,
481 12
765 12
3 12
701 13
482 13 V482A,
764 13
9 13 A9V, A9T,
680 13
402 13 H402R,
681 13 R681W,
728 13
703 13
10 14
720 14
768 14
731 14 H731R,
677 14 M677T,
476 14 V476I,
404 15
401 15
683 15