KCNH2 Variant H674Q Detail

We estimate the penetrance of LQTS for KCNH2 H674Q is 10%. We are unaware of any observations of this variant in individuals. H674Q is not present in gnomAD. H674Q 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 H674Q around 10% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.75 0.784 0 0.83 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 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.

H674Q has 51 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
674 0 H674Y, H674fsX,
673 4
675 6
671 6 A671G, A671Del,
670 6
677 6 M677T,
543 7 S543fsX,
678 7
665 7 R665Q,
669 8 G669C, G669R, G669X,
676 8 Q676fsX, Q676X,
672 8 R672H, R672C,
544 9 E544A, E544fsX,
681 9 R681W,
540 9 D540fsX,
546 10
705 10 W705fsX, W705X,
549 10 V549M,
662 10
668 10 S668L,
701 11
679 11 R679Q, R679W,
539 11
702 11
680 11
545 12
667 12 Y667X,
661 12 A661V,
3 12
658 12
710 12
666 12
664 12 Q664X,
548 12
682 13 E682X,
547 13 A547T,
542 13
698 13 E698X, E698K,
668 13 S668L,
4 14
541 14 R541C, R541H,
706 14 S706F, S706C,
709 14
550 14
664 14 Q664X,
553 14 L553V,
659 14
663 15
552 15 L552S,
704 15 A704T, A704V,
666 15