KCNH2 Variant K718N Detail

We estimate the penetrance of LQTS for KCNH2 K718N is 23%. We are unaware of any observations of this variant in individuals. K718N is not present in gnomAD. K718N 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 K718N around 23% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.854 0.879 0 0.682 30
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.

K718N has 34 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
718 0
715 5 A715T, A715sp, A715A, A715V,
717 5 L717P,
719 6
716 6 V716G,
714 6
720 8
725 8 Q725R, Q725fsX,
721 9 P721L,
712 10 D712N,
713 10 M713V,
722 11
756 11 M756V,
679 12 R679W, R679Q,
724 12 L724X,
728 12
712 12 D712N,
683 12
676 12 Q676X, Q676fsX,
714 12
729 13
726 13
700 13
680 13
711 13 I711V,
701 14
723 14 C723R, C723X, C723G,
697 14 L697X,
715 14 A715T, A715sp, A715A, A715V,
759 14 K759N, K759N,
757 15
704 15 A704T, A704V,
713 15 M713V,
755 15