KCNH2 Variant E682K Detail

We estimate the penetrance of LQTS for KCNH2 E682K is 13%. We are unaware of any observations of this variant in individuals. E682K is not present in gnomAD. E682K 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 E682K around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.889 0.969 1 0.944 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.

E682K has 47 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
682 0 E682X,
678 6
685 6 R685P, R685C, R685H,
711 6 I711V,
709 7
680 7
681 7 R681W,
679 7 R679W, R679Q,
683 7
684 7
686 8
710 8
708 9
677 9 M677T,
713 10 M713V,
668 10 S668L,
675 10
687 10
669 10 G669C, G669R, G669X,
712 10 D712N,
676 10 Q676fsX, Q676X,
716 10 V716G,
672 11 R672H, R672C,
705 11 W705fsX, W705X,
665 11 R665Q,
666 11
707 12
688 12
689 12
706 12 S706C, S706F,
674 13 H674Y, H674fsX,
715 13 A715V, A715A, A715T, A715sp,
694 13 R694H, R694C,
546 13
697 13 L697X,
670 13
545 13
698 13 E698X, E698K,
544 13 E544A, E544fsX,
701 14
667 14 Y667X,
717 14 L717P,
673 14
704 14 A704T, A704V,
714 14
671 14 A671Del, A671G,
720 15