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
9042910 Edwards et al (1997) catalogued 25 TCOF1 variants, all but one resulting in the introduction of a premature-termination codon.
12114482 Splendore et al (2002) observed that the majority of pathogenic variants are small deletions and insertions causing frameshifts that are predicted to result in a truncated protein and that more than 50% of all described pathogenic variants known at the time were clustered in five exons (10, 15, 16, 23, and 24).
15340364 Teber et al (2004) assessed 36 patients with a clinically unequivocal diagnosis of Treacher-Collins syndrome (TCS), and detected 28 pathogenic variants, including 25 novel alterations. Most of the variants were predicted to lead to premature termination codons because of frameshift length alterations (variants in 14 patients) or nonsense substitutions (variants in six patients). Variants identified in five patients affected invariable bases at splice donor (n=2) or acceptor (n=3) sites. No variant was identified in the remaining eight patients with unequivocal diagnosis of TCS and 10 further patients, in whom the referring diagnosis of TCS was clinically doubtful.
8875242 Dixon et al (1996) catalogued 20 variants all resulting in the introduction of a premature stop codon in patients with a clinical diagnosis of Treacher Collins syndrome, supporting a mechanism of haploinsufficiency.
22317976 Bowman et al (2012) assessed 182 patients with clinical features consistent with TCS, and identified 92 pathogenic sequence level variants (57% frameshift, 23% nonsense, 16% splicing, 4% missense), as well as 5 partial gene deletions. Many of the sequence variants arose de novo.

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.