ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
10777716 Wenstrup RJ (2000). Eight of 28 probands with classical EDS who were heterozygous for expressed variants in COL5A1 showed complete or nearly complete loss of expression of one COL5A1 allele. Frameshift mutations, nonsense mutations and deletion of amino acids 38-92 were identified in several patients (see table 1). They estimate that approximately one-third of individuals with classical EDS have mutations of COL5A1 that result in haploinsufficiency. Several lines of evidence suggest that haploinsufficiency of COL5A1 can produce classical EDS. First, gross interruption of the COL5A1 gene, reported in one case, produced classical EDS (Toriello et al. 1996). Second, the reported primary structure changes in the carboxyl-terminal propeptide of the pro-a1(V) chain in several families with classical EDS were likely to prevent the mutant chains from being included in trimeric type V collagen molecules (Wenstrup et al. 1996; De Paepe et al. 1997).
8673139 Toriello et al. (1996) describe a balanced translocation between chromosome 9 and an X chromosome that disrupts the minor fibrillar collagen type V gene COL5A1 in a patient with both EDS type I and hypomelanosis of Ito. The breakpoint occurs at 9q34 within COL5A1 intron 24 and interestingly, within a LINE-1 (L1) element at Xp21.1. A fusion mRNA between COL5A1 and an Alu sequence is produced, but no aberrant protein is detectable. Rather, the amount of type V collagen is reduced in the patient's fibroblasts, suggesting haploinsufficiency as a cause of the phenotype.
10796876 Schwarze U (2000). They analyzed variants in the COL5A1 gene in 16 individuals, and they examined mRNA for the expression of both alleles and for alterations in splicing. they found a splice-site mutation in a single individual, and determined that, in six individuals, the mRNA from one COL5A1 allele either was not expressed or was very unstable. They identified small insertions or deletions in five of these cell strains, but we could not identify the mutation in the sixth individual. Thus, although as many as one-half of the mutations that give rise to EDS types I and II are likely to lie in the COL5A1 gene, a significant portion of them result in very low levels of mRNA from the mutant allele, as a consequence of nonsense-mediated mRNA decay.

Haploinsufficiency phenotype comments:

The most common types of molecular defect lead to haploinsufficiency for COL5A1 mRNA. In approximately 40% of individuals with classic EDS, nonsense or frameshift variants are responsible for a non-functional COL5A1 allele [Schwarze et al 2000, Wenstrup et al 2000, Schwarze et al 2001, Malfait et al 2005]. Nonsense, frameshift, or splice-site variants that introduce a premature termination codon are usually responsible for this non-functional COL5A1 allele. COL5A1 null alleles are detected in approximately 30%-40% of individuals with classic EDS [Malfait et al 2005]. No deletions or duplications involving COL5A1 as causative of classic EDS have been reported. In some families with a non-functional (i.e., null) COL5A1 allele, an affected member can have a very mild classic EDS phenotype, while other family members may have a severe phenotype [Malfait & De Paepe 2005].

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