ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000011.9) (NC_000011.10)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
22241717 SDHAF2 (also known SDH5) is a tumor suppressor gene which encodes for a protein required for flavination of a succinate dehydrogenase subunit. A novel frameshift mutation was reported by Piccini et al 2012 (PMID: 22241717) in a 44-year-old woman diagnosed with paraganglioma, but with a negative family history. In exon 4, she had c.357-358insT (p.Tyr119LeufsX7) mutation which has not been observed in other patients and there was no indication that other family members were tested.
26096992 Zhu et al 2015 (PMID 26096992) assessed the frequency of germline mutations in Chinese patients with head and neck paragangliomas (HNPGL) without family history. They identified one female patient who had early age of onset of HNPGL who had a novel truncation mutation c.130C>T (p.Gln44Ter).

Haploinsufficiency phenotype comments:

In a Dutch kindred and a Spanish family (proven to be unrelated by high-density SNP array of 610,000 SNPs) with early onset of head and neck paragangliomas (Hao et al (2009), PMID 19628817 and Bayley et al (2010), PMID 20071235), all affected family members were found to inherit a c.232G>A change in exon 2, which caused a Gly78Arg (G78R) mutation. Of note, this variant was not identified in 400 unaffected controls. There is notable parent-of-origin effect given that the phenotype is only expressed when paternally inherited. In both families, it is not expressed when the mutation is maternally inherited. Mulitplex-PCR for large deletions of SDHAF2 in 200 patients did not detect any deletions. (Bayley et al (2010), PMID 20071235). A novel frameshift mutation has been reported in a patient with nonsyndromic paraganglioma and a novel truncation mutation has been reported in a patient with benign HNPGLs. Their phenotype is consistent with that of affected patients from 2 large families with a recurrent missense mutation in the same SDHAF2 gene.

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