KCNH2 Variant H703Q Detail

We estimate the penetrance of LQTS for KCNH2 H703Q is 15%. We are unaware of any observations of this variant in individuals. H703Q is not present in gnomAD. H703Q 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 H703Q around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.643 0.902 0 0.638 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.

H703Q has 58 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
703 0
704 4 A704T, A704V,
706 6 S706C, S706F,
700 6
764 7
707 7
702 7
699 7 E699D, E699D,
827 7
762 7
701 8
763 8
705 9 W705fsX, W705X,
708 9
765 9
4 9
478 9 A478D,
767 10 D767X,
6 10 G6R,
481 11
709 11
479 11
828 11
698 11 E698K, E698X,
761 11
697 11 L697X,
7 12
829 12 D829E, D829E, D829A,
766 12
826 12 T826A, T826I,
720 12
710 12
480 12 E480V,
696 12 R696H, R696C,
686 12
721 12 P721L,
673 12
476 12 V476I,
719 12
477 13
5 13
824 13
724 13 L724X,
760 13
711 13 I711V,
830 13
695 13
677 14 M677T,
713 14 M713V,
482 14 V482A,
8 14
825 14
3 14
676 14 Q676X, Q676fsX,
769 15
768 15
784 15 R784Q, R784G, R784W,
723 15 C723G, C723X, C723R,