ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000011.9) (NC_000011.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
26669661 Itoh et al. (2016) A study of multi-national cohort of LQTS families described asymmetry of parental origin in long QT syndrome, with preferential maternal transmission of KCNQ1 variants linked to channel dysfunction. There were a total of 35 LQT1 patients with LOF variants in KCNQ1 gene selected for this study: nonsense (n=6), splice site (n=7), and frameshift variants (n=22) with known or assumed loss of function.
29532034 Huang et al. (2018) studied the mechanisms of KCNQ1 channel dysfunction in LQT. A total of 32 LOF variants (missense or in-frame) were studied with an emphasis on elucidating effects on cell surface expression, protein folding, and structure. More than half of the KCNQ1 LOF mutations examined were seen to destabilize the structure of the voltage sensor domain (VSD), generally accompanied by mistrafficking and degradation by the proteasome, an observation that underscores the growing appreciation that mutation-induced destabilization of membrane proteins may be a common human disease mechanism.
23098067 Stattin et al. (2012) studied 200 Swedish LQT Probands aiming to report the spectrum of LQTS mutations in this Swedish cohort. . Thirty KCNQ1 variants were identified, 9 of which were LOF variants.

Haploinsufficiency phenotype comments:

Heterozygous loss of function variants can cause long QT syndrome type 1. Biallelic variation in KCNQ1 can result in the recessive condition Jervell and Lange-Nielsen syndrome. Numerous LOF variants in KCNQ1 have been reported in the literature and public/commercial databases. Additional evidence includes: PMID: 18774102. Barc (2011): Describes a single 2 exon deletion in a patient with long QT syndrome type 1. PMID: 18774102. Eddy (2008): Describes a single 2 exon deletion resulting in a frameshift and premature stop codon in a patient with long QT syndrome type 1. PMID:15840476 Tester (2005): Describes 88 patients with long QT syndrome and variants in KCNQ1. Fourteen of these are either nonsense or frameshift mutations.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity