KCNH2 Variant Q702E Detail

We estimate the penetrance of LQTS for KCNH2 Q702E is 11%. We are unaware of any observations of this variant in individuals. Q702E is not present in gnomAD. Q702E 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 Q702E around 11% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.863 0.243 2 0.764 16
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.

Q702E has 62 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
702 0
701 5
4 5
698 7 E698X, E698K,
699 7 E699D, E699D,
703 7
705 7 W705fsX, W705X,
706 7 S706C, S706F,
704 7 A704T, A704V,
673 7
677 8 M677T,
700 8
3 9
5 9
6 9 G6R,
697 9 L697X,
680 11
476 11 V476I,
676 11 Q676X, Q676fsX,
674 11 H674fsX, H674Y,
540 11 D540fsX,
708 11
695 11
681 11 R681W,
481 11
478 11 A478D,
709 11
707 12
710 12
764 12
694 12 R694C, R694H,
720 12
544 12 E544A, E544fsX,
670 12
7 12
696 13 R696H, R696C,
669 13 G669R, G669X, G669C,
827 13
672 13 R672C, R672H,
678 13
765 13
719 13
543 13 S543fsX,
675 14
477 14
402 14 H402R,
541 14 R541H, R541C,
480 14 E480V,
762 14
403 14
482 14 V482A,
479 14
671 14 A671G, A671Del,
767 14 D767X,
693 14 L693X,
724 14 L724X,
763 14
684 14
711 15 I711V,
679 15 R679Q, R679W,
539 15
721 15 P721L,