ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.79C>T (p.Arg27Ter) (rs74315369)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129929 SCV000184747 pathogenic Hereditary cancer-predisposing syndrome 2020-09-04 criteria provided, single submitter clinical testing The p.R27* pathogenic mutation (also known as c.79C>T), located in coding exon 2 of the SDHB gene, results from a C to T substitution at nucleotide position 79. This changes the amino acid from an arginine to a stop codon within coding exon 2. The predicted stop codon occurs within the first 150 nucleotides of SDHB gene. This alteration may escape nonsense-mediated mRNA decay and/or be rescued by re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653), and it impacts the first 57 amino acids of the protein. However, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). This mutation has previously been reported in multiple cases of both sporadic and familial PGL-PCC as well as renal cell carcinoma (Cascón A et al. J. Med. Genet., 2002 Oct;39:E64; Vanharanta S et al. Am. J. Hum. Genet., 2004 Jan;74:153-9; Neumann HP et al. JAMA, 2004 Aug;292:943-51; Naito M et al. Endocrine, 2009 Aug;36:10-5; Graham D et al. Case Rep Genet, 2014 Aug;2014:273423; Casey RT et al. J. Clin. Endocrinol. Metab., 2017 11;102:4013-4022; Fife K et al. BMJ Case Rep, 2017 Aug;2017; Benn DE et al. J. Med. Genet., 2018 11;55:729-734; Albattal S et al. Oncotarget, 2019 Oct;10:5919-5931). Functional studies of this alteration have demonstrated the absence of SDH enzymatic activity as well as the absence of SDHB protein in cell-based assays, indicating nonsense-mediated mRNA decay or protein degradation as a mechanism for absent enzymatic activity (Kim E et al. Endocr. Relat. Cancer, 2015 Jun;22:387-97). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000471400 SCV000554026 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2018-09-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg27*) in the SDHB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs74315369, ExAC 0.006%). This variant has been observed in individuals affected with pheochromocytoma (PMID: 12000816, 25215250, 12362046), paraganglioma (PMID: 18382370, 14685938, 19415531), and early-onset renal cell cancer (PMID: 14685938). This variant is also known as C213T in the literature. ClinVar contains an entry for this variant (Variation ID: 12783). Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000657585 SCV000779322 pathogenic not provided 2019-10-17 criteria provided, single submitter clinical testing Observed in individuals with pheochromocytoma and/or paraganglioma as well as in an individual with early-onset renal cell carcinoma (Cascn 2002, Neumann 2004, Vanharanta 2004, Klein 2008, Naito 2009, Merlo 2013, Graham 2014, Jochmanova 2017); Published functional studies demonstrate a damaging effect: absent SDHB protein production, absent SHD enzymatic activity, and abolished association with SDHA (Kim 2015); 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; Also known as SDHB 213C>T; This variant is associated with the following publications: (PMID: 31579262, 12000816, 19184535, 26916530, 25972245, 12362046, 14685938, 15476441, 15328326, 18728280, 17102084, 12213855, 22517557, 25215250, 23902947, 19343621, 19415531, 18382370, 28374168, 30694796, 31666924, 31492822, 29625052, 31447099)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000013623 SCV000840069 pathogenic Paragangliomas 4 2018-02-06 criteria provided, single submitter clinical testing This c.79C>T (p.R27*) variant is predicted to result in a premature stop codon and has been reported in individuals with pheochromocytoma, paraganglioma and early-onset renal cell cancer (PMID: 12000816, 25215250, 18382370, 14685938, 14685938). In addition, in vitro studies have shown that the c.79C>T (p.R27*) variant alters SDHB expression and function. Therefore we classify this variant as pathogenic.
OMIM RCV000013623 SCV000033870 pathogenic Paragangliomas 4 2002-05-09 no assertion criteria provided literature only
OMIM RCV000013624 SCV000033871 pathogenic Pheochromocytoma 2002-05-09 no assertion criteria provided literature only
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505368 SCV000599488 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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