ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1686C>G (p.His562Gln) (rs1057520477)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000434772 SCV000515600 likely pathogenic not provided 2016-10-21 criteria provided, single submitter clinical testing A novel H562Q variant that is likely pathogenic was identified in the KCNH2 gene. This variant hasnot been published as a pathogenic variant, nor has it been reported as a benign variant to ourknowledge. The H562Q variant was not observed in approximately 6,500 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a commonbenign variant in these populations. The H562Q variant is a semi-conservative amino acidsubstitution, which may impact secondary protein structure as these residues differ in some properties.This substitution occurs at a position that is conserved across species, and in silico analysis predictsthis variant is probably damaging to the protein structure/function. In addition, simulations byLees-Miller et al. (2009) demonstrated that the H562 residue, located within the trans-membranehelix of segment S5, connects the S5 helix to the pore helix, which stabilizes the pore domain andplays an important role in the structure/function of the potassium channel. Variants affecting theH562 residue are thought to lead to a disruption of the hydrogen bonding to amino acids within thepore helix, resulting in distortion of the selectivity filter (Lees-Miller et al., 2009). Furthermore,missense variants in nearby residues (A558E, A561P, A561T, A561V) and different missense variantsat the same residue (H562P, H562R) have been reported in the Human Gene Mutation Database inassociation with LQTS (Stenson et al., 2014), supporting the functional importance of this residue andregion of the protein.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance,additional data is required.

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