ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

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.

Evidence for Triplosenstive Phenotype

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.