ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.