SDHAF2

Gene Facts

• HGNC Symbol: SDHAF2 (HGNC:26034)
• HGNC Name: succinate dehydrogenase complex assembly factor 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: PGL2, C11orf79
• Alias symbols: FLJ20487, SDH5
• %HI: 7.74
• pLI: 0
• LOEUF: 1.61
• Cytoband: 11q12.2
• Genomic Coordinates:

  GRCh37/hg19:	chr11:61197596-61214205
  GRCh38/hg38:	chr11:61430124-61446733

• MANE Select Transcript: NM_017841.4 ENST00000301761.7
• Function: Plays an essential role in the assembly of succinate dehydrogenase (SDH), an enzyme complex (also referred to as respiratory complex II) that is a component of both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain, and which couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol. Required for flavinylation (covalent attachment of FAD) of the flavoprotein subunit SDHA of the SDH catalytic dimer. {ECO:0000255|HAMAP... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-28759
• ClinGen Curation ID: CCID:007813
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 05/11/2022

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Evidence

• PUBMED: 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 variant 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) variant which has not been observed in other patients and there was no indication that other family members were tested.
• PUBMED: 26096992
  Zhu et al 2015 (PMID 26096992) assessed the frequency of germline variants 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 variant c.130C>T (p.Gln44Ter).
• PUBMED: 31687641
  Wolf KI et al (2019) describe a 30-year-old female diagnosed with paraganglioma with a novel SDHAF2 variant c.347G>A;p.W116X, which was confirmed with sanger sequencing. This nonsense variant is predicted to cause a truncated protein that affects a conserved domain of the protein. The proband had 2 siblings who also had this variant, one had papillary thyroid carcinoma and the other had follicular adenoma.

• HI Evidence 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) variant. 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 variant is maternally inherited. Multiplex-PCR for large deletions of SDHAF2 in 200 patients did not detect any deletions. (Bayley et al (2010), PMID 20071235). Bausch et al (2017) found a 25 year old female from United States with germ line c.232G>A variant having head and neck paraganglioma. (PMID: 28384794) A novel frameshift variant has been reported in a patient with nonsyndromic paraganglioma and a novel truncation variant 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 variant in the same SDHAF2 gene. (PMID: 26269449)

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity