ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000007.13) (NC_000007.14)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
21862832 Yu and Graf (2011) report a patient with a history of oligohydramnios, normal birth weight, feeding difficulties and failure to thrive, small hyperpigmented macules, sparse hair, skeletal anomalies, seizures, profound intellectual disability, and hypotonia. The authors note that many of the features present in this patient are not consistent with Cardiofacialcutaneous syndrome (cause by gain of function missense mutations in BRAF). Chromosomal microarray detected a 93 kilobase intragenic deletion in BRAF. Parental specimens were not available for testing. No other genetic studies (other than a normal karyotype) were reported. The authors suggest haploinsufficiency of BRAF as an explanation for the patient's features. Functional studies were not done but, if a truncated protein were stable, it would lack all domains necessary for upstream or downstream activation within the RAS-MAPK pathway and would not be able to heterodimerize.

Haploinsufficiency phenotype comments:

Heterozygous gain of function missense mutations and rare in-frame deletions which lead to elevated kinase activity are a cause of Cardiofacialcutaneous (CFC) syndrome, LEOPARD syndrome, and Noonan syndrome. Some missense mutations can lead to reduced kinase activity, measured by luciferase assays using an ELK-dependent vector (PMID:16474404), and reduced phosphorylation of downstream effectors in transfected cells (PMID:18470943). Yu and Graf (2011) discuss this phenomenon as possible evidence that deletion of BRAF could lead to a viable, abnormal phenotype in human. However, Moretti, et al., 2009 (PMID:19735675) demonstrated that missense mutants, transfected into HEK293T cells, which have reduced kinase activity, are able to heterodimerize with C-Raf and induce its transactivation. Therefore, the functional effects of these BRAF missense mutations are still being elucidated and it is not clear whether a deletion of BRAF might lead to disruption or dysregulation of the RAS-MAPK pathway. BRAF mutations, including point mutations, deletions, and duplications, are frequently found as acquired abnormalities in a variety of tumors.

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

Triplosensitivity phenotype comment:

While there are rare reports of large duplications of 7q that include BRAF in individuals with a variety of congenital abnormalities and other cytogenetic abnormalities (PMIDs: 22161098, 22482977, 19838731, 2248294, 2319577), to our knowledge, congenital focal whole gene duplications of BRAF have not been reported in the literature. BRAF mutations, including point mutations, deletions, and duplications, are frequently found as acquired abnormalities in a variety of tumors.