KCNH2 Variant Q664R Detail

We estimate the penetrance of LQTS for KCNH2 Q664R is 14%. We are unaware of any observations of this variant in individuals. Q664R is not present in gnomAD. Q664R 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 Q664R around 14% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.876 0.997 1 0.935 19
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.

Q664R has 46 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
664 0 Q664X,
661 5 A661V,
663 5
660 6 S660L,
668 7 S668L,
662 7
671 7 A671Del, A671G,
667 7 Y667X,
665 7 R665Q,
658 8
666 8
657 8 G657V, G657S,
654 9
659 9
670 9
669 10 G669R, G669C, G669X,
661 10 A661V,
657 10 G657V, G657S,
672 10 R672C, R672H,
658 10
653 11
660 12 S660L,
655 12
662 12
675 12
665 12 R665Q,
546 12
659 12
674 12 H674Y, H674fsX,
675 13
550 13
664 13 Q664X,
664 13 Q664X,
656 13 F656L, F656L, F656L,
650 13 L650X,
671 13 A671Del, A671G,
547 14 A547T,
656 14 F656L, F656L, F656L,
678 14
549 14 V549M,
673 14
651 14 M651K,
553 14 L553V,
674 14 H674Y, H674fsX,
655 15
660 15 S660L,