Submissions for variant NM_003000.3(SDHB):c.268C>T (p.Arg90Ter)

gnomAD frequency: 0.00001  dbSNP: rs74315366

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037718	SCV000053299	pathogenic	Hereditary pheochromocytoma-paraganglioma	2022-05-17	criteria provided, single submitter	clinical testing	Variant summary: SDHB c.268C>T (p.Arg90X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251336 control chromosomes (gnomAD). c.268C>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (e.g. Astuti_2001, Benn_2006, Andrews_2018). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant has no protein activity (Kim_2015). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037718	SCV000061380	pathogenic	Hereditary pheochromocytoma-paraganglioma	2019-03-21	criteria provided, single submitter	clinical testing	The p.Arg90X variant in SDHB has previously been identified in at least 12 individuals with SDHB-associated tumors and segregated with disease in 9 affected family members from at least 5 families (Amar 2005, Zu 2011, Srirangalingam 2008, Benn 2006, Hensen 2012, Elston 2017, Gill 2011, Lee 2014, Crona 2014, Burnichon 2009, Benn 2003). It has also been identified in 2/113664 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 12778). This nonsense variant leads to a premature termination codon at position 90, which is predicted to lead to a truncated or absent protein. Functional studies support an impact on protein function (Kim 2015, Elston 2017). Heterozygous loss of function of the SDHB gene is an established disease mechanism in patients with hereditary paraganglioma and pheochromocytoma. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary paraganglioma and pheochromocytoma. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate, PS3_Supporting.
GeneDx	RCV000183211	SCV000235630	pathogenic	not provided	2021-12-10	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(R62*); This variant is associated with the following publications: (PMID: 26332594, 27573198, 17102068, 20061288, 25371406, 27171833, 16314641, 18419787, 25972245, 25525159, 22517557, 11404820, 28324028, 26230854, 21934479, 26464466, 23083876, 28374168, 19454582, 28973655, 15328326, 19576851, 12618761, 16317055, 24659481, 28748451, 30050099, 31666924, 31492822, 32804377, 32741965, 30787465, 33726816)
UCLA Clinical Genomics Center, UCLA	RCV000013616	SCV000255462	pathogenic	Paragangliomas 4	2014-01-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000215883	SCV000274572	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-05	criteria provided, single submitter	clinical testing	The p.R90* pathogenic mutation (also known as c.268C>T), located in coding exon 3 of the SDHB gene, results from a C to T substitution at nucleotide position 268. This changes the amino acid from an arginine to a stop codon within coding exon 3. This pathogenic mutation has been reported in multiple unrelated families exhibiting pheochromocytomas and/or paragangliomas (Astuti D et al. Am J Hum Genet. 2001 Jul;69(1):49-54; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91:827-36; Ricketts CJ et al. J Urol. 2012 Dec;188(6):2063-71; Crona J et al. PLoS One. 2014 Jan;9(1):e86756; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143(8):1421-1435; Albattal S et al. Oncotarget. 2019 Oct 15;10(57):5919-5931). This mutation has also been identified in a woman with a renal tumor and family history of paragangliomas, where the renal tumor demonstrated negative SDHB staining by immunohistochemistry (Gill AJ et al. Am. J. Surg. Pathol. 2011 Oct;35:1578-85). It was recently seen in a patient with a duodenal GIST who also had a family history of paragangliomas. IHC analysis of the GIST showed negative SDHB staining, and the tumor was positive for the p.R90* mutation (Elston MS et al. J. Clin. Endocrinol. Metab. 2017 May;102(5):1447-1450). In vitro data showed complete loss of SDHB expression in cytosolic and mitochondrial compartments as well as no measurable SDH activity in cells transfected with this truncating mutation (Kim E et al. Endocr. Relat. Cancer 2015 Jun;22:387-97). Of note, this mutation is referred to as p.R91X in the Astuti (2001) paper. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627749	SCV000554022	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg90*) in the SDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). This variant is present in population databases (rs74315366, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with pheochromocytoma, paraganglioma and renal cell carcinoma (PMID: 11404820, 12618761, 16314641, 16317055, 18419787, 19454582, 21348866, 21934479, 23083876, 24466223, 25326637). This variant is also known as R91X. ClinVar contains an entry for this variant (Variation ID: 12778). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763272	SCV000893916	pathogenic	Carney-Stratakis syndrome; Paragangliomas 4; Pheochromocytoma	2018-10-31	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000183211	SCV002760634	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000013616	SCV002761844	pathogenic	Paragangliomas 4	2022-05-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000183211	SCV002774863	pathogenic	not provided	2021-08-18	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of SDHB protein synthesis. In the published literature, the variant has been reported in individuals with paraganglioma, pheochromocytoma, gastrointestinal stromal tumor, and renal cell carcinoma (PMIDs: 28374168 (2017), 28324028 (2017), 23083876 (2012), 19454582 (2009), 18419787 (2008), and 11404820 (2001)). Therefore, the variant is classified as pathogenic.
Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	RCV003233026	SCV003930413	pathogenic	Von Hippel-Lindau syndrome	2023-05-10	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000013616	SCV004806426	pathogenic	Paragangliomas 4	2024-03-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000013616	SCV004933588	pathogenic	Paragangliomas 4	2024-02-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
OMIM	RCV000013616	SCV000033863	pathogenic	Paragangliomas 4	2001-07-01	no assertion criteria provided	literature only
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000037718	SCV000599490	pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research