KCNH2 Variant N658K Detail

We estimate the penetrance of LQTS for KCNH2 N658K is 31%. We are unaware of any observations of this variant in individuals. N658K is not present in gnomAD. N658K 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 N658K around 31% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.681 0.995 0 0.784 40
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 7 3 -
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.

N658K has 59 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
658 0
657 4 G657V, G657S,
659 5
655 6
661 6 A661V,
654 6
660 6 S660L,
662 6
656 7 F656L, F656L, F656L,
553 7 L553V,
664 8 Q664X,
653 8
660 9 S660L,
663 9
549 9 V549M,
550 9
665 9 R665Q,
663 10
651 10 M651K,
671 10 A671Del, A671G,
664 10 Q664X,
661 11 A661V,
667 11 Y667X,
653 11
652 11 Y652X,
554 11
552 11 L552S,
670 12
546 12
650 12 L650X,
659 12
654 12
674 12 H674fsX, H674Y,
650 12 L650X,
556 12
557 12
543 13 S543fsX,
657 13 G657V, G657S,
668 13 S668L,
666 13
547 13 A547T,
548 13
662 13
657 13 G657V, G657S,
649 13
666 13
675 14
555 14
669 14 G669C, G669X, G669R,
656 14 F656L, F656L, F656L,
551 14 F551L, F551L, F551L,
539 14
648 14 G648A,
649 14
658 15
658 15
665 15 R665Q,
672 15 R672C, R672H,
667 15 Y667X,