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
12567410 Savarirayan et al. (2003) identified a heterozygous 1-bp insertion in the GDF5 gene, 206insG, in 8 members of 3 unrelated families with type C brachydactyly. This mutation results in a frameshift and premature termination 25 amino acids downstream. The change was not detected in 100 control alleles.
9288091 Polinkovsky et al. (1997) identified a heterozygous C-to-T transition at nucleotide 901 of the GDF5 mRNA coding sequence in affected members of a family with brachydactyly type C. The mutation results in a R301X substitution.
18283415 Yang et al (2008) identified a T-to-G transversion in GDF5 in a 4 generation family with brachydactyly type C. The mutation was not detected in unaffected family members or 50 controls. The mutation results in a Y487X substitution that is predicted to truncate the precursor polypeptide by 15 amino acids.

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.