KCNH2 Variant N714K Detail

We estimate the penetrance of LQTS for KCNH2 N714K is 21%. We are unaware of any observations of this variant in individuals. N714K is not present in gnomAD. N714K 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 N714K around 21% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.719 0.813 0 0.595 28
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 8 2 -
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.

N714K has 43 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
714 0
715 5 A715sp, A715V, A715T, A715A,
713 5 M713V,
717 6 L717P,
718 6
712 7 D712N,
716 7 V716G,
759 10 K759N, K759N,
711 10 I711V,
725 10 Q725fsX, Q725R,
683 10
760 10
719 11
729 11
756 11 M756V,
720 11
728 11
708 11
679 12 R679Q, R679W,
719 12
687 12
732 12
710 12
686 12
718 12
757 13
755 13
761 13
758 13
726 13
680 13
707 13
721 13 P721L,
832 14
722 14
704 14 A704T, A704V,
724 14 L724X,
733 14
682 14 E682X,
676 14 Q676X, Q676fsX,
762 15
709 15
721 15 P721L,