Inheritance

Autosomal recessive / autosomal dominant / X-linked

Prevalence

  1-9 / 1 000 000

Source:ORPHA:29072

Rapid or full curation?

•  Rapid
•  Full

ClinGen / GenCC / BabySeq / HGMD

ClinGen Hereditary Cancer GCEP, accessed 07.10.2023

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

Segregation Evidence:

Case/Control Evidence:

Experimental Evidence:

Source:

Clinical Validity Points Total

Source: Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] are associated with an increased risk of multiple paragangliomas and pheochromocytomas tumors within multiple organ systems transmitted in autosomal dominant inheritance. The molecular mechanism is loss of function in one of the 4 genes comprising the succinate dehydrogenase and SDHAF gene for flavination of SDHA, as well as stabilization of the SDH complex. SDHC encodes one of the 4 subunits of SDH (succinate dehydrogenase), one of the two small integral membrane proteins in the mitochondrial complex II. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, this is a lumping Curation for SDHC and SDHC associated Hereditary Paraganglioma-Pheochromocytoma syndromes (PGL/PCC) including autosomal dominant inherited Paraganglioma 3 (MIM: 605373) and Gastrointestinal stromal tumor (MIM: 606764). SDHC was first reported in relation to PGL/PCC in 2000 [Niemann and Muller et al., PMID: 11062460]. Three nonsense, two initiation codon, three missense, one splicing and one deletion variants are included in this curation [PMID: 11062460, 15342702, 29386252 and 16405730]. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by experimental evidence. Absent expression of SDHB, the iron protein, catalytic component of mitochondrial complex II were reported in 5 PGL/PCC patients carrying SDHC germline variants [PMIDs: 19576851 and 20236688]. Loss of the complex II SDH (succinate dehydrogenase) and SQR (succinate coenzyme Q oxidoreductase) enzyme activities were shown in Hela cells and Chinese hamster B9 cells transfected with two SDHC mutants, His127Ala and His127Tyr. The absence of SDH and SDR activities in SDHC targeted shRNA Hela and B9 cells can be rescued by wt SDHC construct, but not by the constructs of the two SDHC mutants [PMID: 19332149]. Knockout mouse homolog of human SDHC is homozygous-lethal [PubMed: 27626380]. In summary, the SDHC gene is definitely associated with autosomal dominant PGL/PCC syndrome. This has been repeatedly demonstrated in both the genetic, and experimental, biochemical and functional studies, and has been upheld over time.

Source: ClinGen Hereditary Cancer GCEP, accessed 07.10.2023

Clinical Validity Points Total

18

Source: ClinGen Hereditary Cancer GCEP, accessed 07.10.2023

Clinical Validity Classification

Definitive

Source: ClinGen Hereditary Cancer GCEP, accessed 07.10.2023

Molecular Mechanism

Loss of function / Gain of function / Dominant Negative

Source: ClinGen Hereditary Cancer GCEP, accessed 07.10.2023, PMID: 29386252, 19332149.

Penetrance

(list source/PMID)

Reduced

Source: PMID: 20301715

Age of Onset

(list source/PMID)

Unclear, but affected individuals present in adulthood.

Source: ClinGen Actionability https://actionability.clinicalgenome.org/ac/Adult/ui/stg2SummaryRpt?doc=AC150 , PMID: 20301715

Severity

Moderate

Clinical Features

• Multiple, multifocal, recurrent, early onset paraganglioma and/or pheochromocytoma and/or a family history.

  • Paragangliomas that arise from neuroendocrine tissue, distributed from the skull base to the pelvic floor.

  • Pheochromocytomas are paragangliomas that are confined to the adrenal medulla. They typically lead to catecholemine excess.

  • Note: Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory.

• Symptoms of PGL/PCC result from effects of catecholamine hypersecretion (sustained or paroxysmal elvations in blood pressure, headach, episodic profuse sweating, forceful palpitations, pallor, and anxiety), palpable abdominal mass, enlarging mass of the skull base/neck, compromise of cranial nerves presenting as hoarseness, dysphagia, soft palate paresis, Horner syndrome; tinnitis.

Sources: PMID: 20301715

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variantSDHC has ≥5 pseudogenes, therefore care should be taken prior to reporting a variant. Technical review and orthogonal confirmation may be needed.

https://www.ncbi.nlm.nih.gov/books/NBK535152/

Curation Summary:

The SDHD gene is associated with autosomal dominant hereditary pheochromocytoma-paraganglioma, which is characterized by multiple, multifocal, recurrent, early onset paraganglioma and/or pheochromocytoma (PMID: 20301715, 29386252, 19332149).

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 07.10.2023