ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.91C>T (p.Arg31Ter) (rs142441643)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131808 SCV000186863 pathogenic Hereditary cancer-predisposing syndrome 2018-03-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000627791 SCV000288157 pathogenic Mitochondrial complex II deficiency; Paragangliomas 5 2019-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 31 (p.Arg31*) of the SDHA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs142441643, ExAC 0.03%). This variant has been reported in multiple individuals with gastrointestinal stromal tumors (GIST), paragangliomas (PGL), pheochromocytomas (PCC), Carney triad (PMID: 26173966), as well as non-PGL tumors (PMID: 21505157, 22955521, 23174939, 21752896, 23666964, 25494863, 26259135). It has also been reported as compound heterozygous in an individual affected with autosomal-recessive complex II deficiency (PMID: 24781757). ClinVar contains an entry for this variant (Variation ID: 142601). Experimental studies have shown that patient-derived cells carrying this variant have decreased SDHA protein expression and mitochondrial complex II enzymatic activity (PMID: 24781757). Loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000413945 SCV000490791 pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing This variant is denoted SDHA c.91C>T at the cDNA level and p.Arg31Ter (R31X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with hereditary paraganglioma-pheochromocytoma syndrome as well as in individuals with SDHA-deficient gastrointestinal stromal tumors (Pantaleo 2011, Korpershoek 2011, Italiano 2012, Rattenberry 2013, Oudijk 2013, Wagner 2013, Batsis 2016, Bahougne 2017, Casey 2017). Additionally, SDHA Arg31Ter has been reported in the compound heterozygous state in an individual with Leigh syndrome (Renkema 2015). We consider this variant to be pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000148026 SCV000677113 pathogenic Paragangliomas 5 2017-11-09 criteria provided, single submitter research
Counsyl RCV000148026 SCV000677772 pathogenic Paragangliomas 5 2015-10-27 criteria provided, single submitter clinical testing
Department of Pediatrics,Memorial Sloan Kettering Cancer Center RCV000148026 SCV000778378 pathogenic Paragangliomas 5 2018-06-06 criteria provided, single submitter clinical testing This mutation was observed in 9 patients in our cancer study. Additional supporting evidence for this mutation contributing to the specific cancers manifested by patients in our cohort, were in the settings of GIST and neuroblastoma. For patients with other cancer types in our cohort, this alteration is suggestive of an independent risk factor for cancers than experienced by the patients.
Geisinger Autism and Developmental Medicine Institute,Geisinger Health System RCV000148026 SCV000804427 pathogenic Paragangliomas 5 2017-06-10 criteria provided, single submitter provider interpretation This 6 year old male with global developmental delays (at-risk for mild intellectual disability), ADHD, disruptive behavior, and mild overgrowth was found to carry a paternally inherited nonsense variant in the SDHA gene. The R31X pathogenic variant in the SDHA gene has been reported previously in the heterozygous state in association with hereditary paraganglioma-pheochromocytoma syndrome (Korpershoek et al., 2011; Rattenberry et al., 2013; Batsis et al., 2016) and in individuals with gastrointestinal stromal tumors (Pantaleo et al., 2011; Wagner et al., 2013; Oudijk et al., 2013). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The patient does not yet show any signs of hereditary paraganglioma-pheochromocytoma syndrome. His father has not yet been formally evaluated, but he reports a history of hypertension.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000722034 SCV000853211 pathogenic Pilocytic astrocytoma 2017-08-24 criteria provided, single submitter clinical testing This is a nonsense alteration in which a C is replaced by a T at coding nucleotide 91 and is predicted to change an Arginine to a premature stop codon at amino acid codon 31. Classification criteria: PVS1, PS1, PP5.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000413945 SCV000884500 pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing The SDHA c.91C>T; p.Arg31Ter variant (rs142441643) is reported in the literature associated with disease in multiple patients. Genetic testing of a gastrointestinal stromal tumor (GIST) in a young adult patient identified the p.Arg31Ter variant in trans from another pathogenic variant (p.Arg589Trp); subsequent testing revealed that the p.Arg31Ter variant was germline whereas the p.Arg589Trp variant was detected only in the tumor (Pantaleo 2011). Another study of paragangliomas (PGL) and pheochromocytomas identified the p.Arg31Ter variant in four tumors (patients were heterozygous for germline p.Arg31Ter, whereas tumors showed loss-of-heterozygosity); however, the same variant was also identified in 0.3% of healthy controls (Korpershoek 2011). A number of other studies have reported the p.Arg31Ter variant in both PGL and non-PGL tumors, often with evidence of p.Arg31Ter as a germline variant in affected patients (Boikos 2016, Denes 2015, Else 2017, Lussey-Lepoutre 2016, Niemeijer 2015, Oudijk 2013, Rattenberry 2013, Wagner 2013). Finally, p.Arg31Ter was also identified in trans from a germline p.Cys189Gly variant in a patient with multisystem mitochondrial disease (Renkema 2015). The p.Arg31Ter variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 142601). It is found in the general population databases with an overall allele frequency of 0.02% (58/276948 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. However, pathogenic heterozygous SDHA variants have incomplete penetrance (Casey 2017) and the individual risk has yet to be determined. REFERENCES Boikos SA et al. Carney triad can be (rarely) associated with germline succinate dehydrogenase defects. Eur J Hum Genet. 2016 Apr;24(4):569-73. Casey RT et al. SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity. Mol Genet Genomic Med. 2017 Mar 2;5(3):237-250. Denes J et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. J Clin Endocrinol Metab. 2015 Mar;100(3):E531-41. Else T et al. Adrenocortical carcinoma and succinate dehydrogenase gene mutations: an observational case series. Eur J Endocrinol. 2017 Nov;177(5):439-444. Korpershoek E et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab. 2011 Sep;96(9):E1472-6. Lussey-Lepoutre C et al. In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma. Clin Cancer Res. 2016 Mar 1;22(5):1120-9. Niemeijer ND et al. Succinate Dehydrogenase (SDH)-Deficient Pancreatic Neuroendocrine Tumor Expands the SDH-Related Tumor Spectrum. J Clin Endocrinol Metab. 2015 Oct;100(10):E1386-93. Oudijk L et al. SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors. Mod Pathol. 2013 Mar;26(3):456-63. Pantaleo MA et al. SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. J Natl Cancer Inst. 2011 Jun 22;103(12):983-7. Rattenberry E et al. A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2013 Jul;98(7):E1248-56. Renkema GH et al. SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors. Eur J Hum Genet. 2015 Feb;23(2):202-9. Wagner AJ et al. Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors. Mod Pathol. 2013 Feb;26(2):289-94.
Fulgent Genetics,Fulgent Genetics RCV000763139 SCV000893699 pathogenic Leigh syndrome; Mitochondrial complex II deficiency; Dilated cardiomyopathy 1GG; Paragangliomas 5 2018-10-31 criteria provided, single submitter clinical testing
GeneReviews RCV000148026 SCV000195526 pathogenic Paragangliomas 5 2014-11-06 no assertion criteria provided literature only
Section on Endocrinology and Genetics,National Institutes of Health / The Eunice Kennedy Shriver National Institute of Child Health and Human Development RCV000170328 SCV000222637 likely pathogenic Carney triad no assertion criteria provided clinical testing
OMIM RCV000148026 SCV000246126 pathogenic Paragangliomas 5 2011-09-01 no assertion criteria provided literature only

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