ClinGen Dosage Sensitivity Curation Page

Gene Information

• id: ISCA-17890
• Date last evaluated: 2015-08-13
• Issue Type: ClinGen Gene Curation
• Gene type: protein-coding
• Entrez Gene: https://www.ncbi.nlm.nih.gov/gene/6392
• OMIM: https://omim.org/entry/602690
• Gene Reviews: https://www.ncbi.nlm.nih.gov/books/NBK1548/?term=SDHD

Location Information

• 11q23.1
• GRCh37/hg19 chr11: 111,957,548-111,966,525
• See linked regions:
• 11q23q25 terminal (Jacobsen syndrome) region

Evidence for Loss Phenotypes

• Loss of function score: 3
• Strength of Evidence: Sufficient evidence for dosage pathogenicity
• Haploinsufficiency phenotype: PARAGANGLIOMAS 1; PGL1

Evidence for loss of function phenotype

PubMed ID	Description
10657297	Baysal et al. 2000 describe SDHD variants in five families with hereditary paraganglioma, including two nonsense variants. The authors report that " none of the mutations has been observed in more than 200 normal control chromosomes...[and that] the mutations cosegregate with the disease phenotype in all affected individuals. "
12111639	Cascon et al. (2002) report variants in SDHD identified in individuals with paraganglioma and/or pheochromocytoma, including one nonsense variant and one "4-bp frameshift deletion in codon 112 (13732delGACT)" that reportedly "gave rise to a 132-amino acid-truncated protein by creating a premature stop codon."

• Loss of function phenotype comments: Several deletions involving SDHD have also been reported, though many of these often include adjacent genes (either in part or in their entirety). For example, McWhinney (2004) et al describe one family with a 96 kb deletion including the entire SDHD gene with a history of paraganglioma (PMID:15531530) . The authors note that this region may also include part of the adjacent TIMM8B gene. Bayley et al (2009) describe two patients with paraganglioma who are deleted for exons 1 and 2 of SDHD as well as the promoter. These deletions also included varying amounts of TIMM8B and other genes (PMID:19546167). Additionally, Caninanos et al (2011) describe one family with paraganglioma and a 25 kb deletion involving the promotor and exons 1 and 2 of SDHD, as well as 5 other genes (DLAT, PIH1D2, C11orf57, TIMM8B, SDHD) (PMID: 20310044).

Evidence for Triplosenstive Phenotype

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

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.