KCNH2 Variant Q576R Detail

We estimate the penetrance of LQTS for KCNH2 Q576R is 63%. We are unaware of any observations of this variant in individuals. Q576R is not present in gnomAD. Q576R 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Q576R around 63% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
1.588 0.004 4 0.596 80
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 4 6 -
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.

Q576R has 31 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
576 0
577 5
573 6
572 6 G572S, G572R, G572C, G572D,
575 6 E575K,
587 8
574 8 M574V, M574L, M574L,
586 8 L586M,
583 9 I583V,
584 9 G584C, G584S, G584R,
597 9 Y597H, Y597C,
571 10 I571V, I571L,
570 11
585 11 W585C, W585C,
569 11 Y569H, Y569C, Y569X,
634 12 T634S, T634I, T634S, T634P, T634A,
637 12 E637G, E637X, E637K,
603 13 G603D,
636 13
605 13 P605L,
604 13 G604S, G604D, G604C,
588 13 N588K, N588K, N588D,
610 13
568 14 W568C, W568C,
590 14 G590D, G590V,
589 14 L589P,
633 14 N633D, N633I, N633S,
596 14 P596L, P596S, P596T, P596R,
635 15 N635I,
430 15
431 15 F431L, F431L, F431L,