KCNH2 Variant N709K Detail

We estimate the penetrance of LQTS for KCNH2 N709K is 18%. We are unaware of any observations of this variant in individuals. N709K is not present in gnomAD. N709K 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 N709K around 18% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.736 0.783 0 0.535 23
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.

N709K has 45 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
709 0
708 4
710 5
705 5 W705fsX, W705X,
711 6 I711V,
706 6 S706C, S706F,
682 7 E682X,
686 7
707 7
669 8 G669R, G669X, G669C,
704 8 A704T, A704V,
672 9 R672C, R672H,
713 10 M713V,
685 10 R685H, R685C, R685P,
668 10 S668L,
712 10 D712N,
673 10
670 10
683 10
703 11
679 11 R679Q, R679W,
687 11
678 11
701 11
702 11
684 12
671 12 A671G, A671Del,
680 13
676 13 Q676X, Q676fsX,
666 13
667 13 Y667X,
681 13 R681W,
688 13
762 13
716 14 V716G,
700 14
674 14 H674fsX, H674Y,
4 14
715 14 A715sp, A715V, A715T, A715A,
714 15
675 15
677 15 M677T,
478 15 A478D,
665 15 R665Q,
675 15