KCNH2 Variant D712E Detail

We estimate the penetrance of LQTS for KCNH2 D712E is 49%. We are unaware of any observations of this variant in individuals. D712E is not present in gnomAD. D712E has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D712E around 49% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.806 0.94 1 0.817 60
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 6 4 -
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.

D712E has 46 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
712 0 D712N,
711 5 I711V,
713 5 M713V,
715 5 A715V, A715A, A715T, A715sp,
710 6
714 7
716 7 V716G,
679 7 R679W, R679Q,
708 8
683 10
718 10
717 10 L717P,
672 10 R672H, R672C,
709 10
682 10 E682X,
719 11
705 11 W705fsX, W705X,
686 11
704 11 A704T, A704V,
676 11 Q676fsX, Q676X,
676 11 Q676fsX, Q676X,
680 12
707 12
718 12
669 12 G669C, G669R, G669X,
719 13
678 13
687 13
675 13
668 13 S668L,
701 13
715 13 A715V, A715A, A715T, A715sp,
720 14
706 14 S706C, S706F,
760 14
720 14
684 14
716 14 V716G,
673 14
679 15 R679W, R679Q,
675 15
700 15
759 15 K759N, K759N,
671 15 A671Del, A671G,
725 15 Q725fsX, Q725R,
677 15 M677T,