KCNH2 Variant Q676K Detail

We estimate the penetrance of LQTS for KCNH2 Q676K is 9%. We are unaware of any observations of this variant in individuals. Q676K is not present in gnomAD. Q676K has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Q676K around 9% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.876 0.773 1 0.783 9
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 10 0 -
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.

Q676K has 47 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
676 0 Q676fsX, Q676X,
679 5 R679W, R679Q,
675 5
677 6 M677T,
673 7
701 7
672 7 R672H, R672C,
680 7
678 7
674 8 H674fsX, H674Y,
716 9 V716G,
705 9 W705X, W705fsX,
710 9
671 9 A671Del, A671G,
715 10 A715A, A715sp, A715V, A715T,
669 10 G669X, G669R, G669C,
719 10
681 10 R681W,
682 10 E682X,
720 11
670 11
702 11
704 11 A704V, A704T,
683 11
712 11 D712N,
665 11 R665Q,
712 11 D712N,
711 12 I711V,
711 12 I711V,
668 12 S668L,
697 12 L697X,
708 12
718 12
700 12
698 12 E698K, E698X,
717 12 L717P,
709 13
706 13 S706C, S706F,
684 13
713 13 M713V,
668 13 S668L,
710 14
672 14 R672H, R672C,
714 14
703 14
544 15 E544fsX, E544A,
543 15 S543fsX,