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 (p.E36X and p.R38X). The authors reported that none of the mutations had been observed in >200 normal control chromosomes and the mutations cosegregated 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 (p.W43X) and one "4-bp frameshift deletion in codon 112 (13732delGACT)" resulting in a truncated protein of 132 amino acids.
11343322	Milunsky et al. (2001) evaluated members of seven families with hereditary paragangliomas. Three loss of function variants were identified: 1) 1-bp insertion (13732insT) in exon 4 in affected members of an Italian family; 2) p.S32X in exon 2 in affected members of an English family; 3) 1-bp deletion (13838delG) in exon 4 in affected members of a German family.
15531530	McWhinney et al. (2004) identified a ~96kb germline whole-gene deletion of SDHD in a 2-generation family with 6 affected individuals with pheochromocytoma and paraganglioma. The authors note that this region may also include part of the adjacent TIMM8B gene. They also identified a 1-kb deletion involving the 5' end of SDHB in another affected family.
12000816	Neumann et al. (2002) identified two nonsense variants (p.C11Xand p.W5X) in the germline of a patient with sporadic pheochromocytoma. These two variants were not identified in 600 control chromosomes.
18211978

• Loss of function phenotype comments: 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.