ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000022.10) (NC_000022.11)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

A recurrent nonsense mutation (Q155X), cause by gene conversion from a nearby pseudogene, has been reported in several families with autosomal dominant cataracts of variable types (PMIDs: 9158139, 10634616, 11424921, 17234267, 18587492, 18449377, 16179907). One patient, reported by Litt et al (2009, PMID: 9158139) was homozygous for this mutation and was more severely affected than her heterozygous relatives. Liu et al (2005, PMID: 15889016) showed that the resulting truncated protein is not degraded and results in some abnormal protein-protein interactions. They reason that at physiologic concentrations, protein-protein interactions would be far more abnormal and potentially lead to aggregation. Another heterzygous nonsense mutation (Y159X) in the same exon was reported by Hanson et al (2009, PMID:19182255) in a family with cataracts. This was predicted to lead to a truncated protein that avoids degradation. These authors also reported another family with sequence changes thought to have been the consequence of gene conversion; however, these results were not reproduced and stated in a later publication (PMID:23011185) to be erroneous. It is not yet clear that the mechanism for cataracts in these families in loss of function and it remains very possible that there is a dominant negative effect responsible.

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

Triplosensitivity phenotype comment:

There are no reports of focal duplications of CRYBB2.