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
11170889 In 2001, Nishimura et al. used sequencing and SSCP analysis on 70 individuals with congenital anterior-chamber defects of the eye for potential FOXC1 variants. These patients had already been screened for causative PITX2 variants and had received negative results. Analysis of FOXC1 identified 9 variants. Per the authors, ?Five of these mutations cause a translational-reading-frame alteration that results in premature termination of the FOXC1 transcript.? For 2 of these variants, segregation was documented to 1 other affected family member. For the other 3 variants, inheritance information was not reported.
17653043 In 2007, Fuse et al. used PCR on a family with Axenfeld-Rieger syndrome to identify potential variants in FOXC1. Analysis discovered a frameshift variant in the proband and her father. This variant is predicted to result in protein truncation, with the protein consisting of 298 amino acids instead of 553 amino acids.
16936096 In 2006, Weisschuh et al. used PCR on 19 patients in 13 families with anterior segment dysgenesis to identify potential variants in PITX2 and FOXC1. Analysis identified 2 frameshift variants leading to premature termination of translation. The authors also identified a nonsense variant leading to protein truncation in another patient.

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.