KCNH2 Variant H578Q Detail

We estimate the penetrance of LQTS for KCNH2 H578Q is 26%. We are unaware of any observations of this variant in individuals. H578Q is not present in gnomAD. H578Q has been functionally characterized in 1 papers. 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 H578Q around 26% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.731 0.002 0 0.665 34
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 8 2 -
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.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
22517356 Xeno 25 -2.5 None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
22517356 Xeno None None None

H578Q 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
578 0
577 4
579 4 M579V, M579I, M579T, M579I, M579I,
576 5
580 5 D580Y,
575 7 E575K,
581 7
574 8 M574V, M574L, M574L,
582 8 R582H, R582C, R582L, R582P,
573 8
583 8 I583V,
572 9 G572D, G572R, G572C, G572S,
584 9 G584S, G584C, G584R,
571 10 I571V, I571L,
585 10 W585C, W585C,
570 11
586 11 L586M,
569 11 Y569H, Y569C, Y569X,
587 11
568 12 W568C, W568C,
588 12 N588K, N588D, N588K,
567 13 I567M, I567T,
589 13 L589P,
566 13 C566G, C566F, C566S, C566S, C566R,
590 13 G590D, G590V,
565 14
591 14 D591N, D591H,
564 14 L564L,
592 14 Q592X,
563 15 W563G, W563C, W563C, W563X,
593 15 I593R, I593K, I593V, I593T, I593X,