ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.88del (p.Gln30fs) (rs747198089)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166126 SCV000216897 pathogenic Hereditary cancer-predisposing syndrome 2019-04-04 criteria provided, single submitter clinical testing ​<span style="background-color:initial">The c.88delC pathogenic mutation, located in coding exon 2 of the SDHB gene, results from a deletion of one nucleotide at position 88, causing a translational frameshift with a predicted alternate stop codon. This alteration has been identified in multiple individuals in the literature who had a personal and/or family history of PGL/PCC (Benn DE et al. J. Med. Genet. 2018 Nov;55(11):729-734; Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394), including <span style="background-color:initial">a 12-year-old male diagnosed with an abdominal PGL/PCC (Benn, DE et al. Oncogene. 2003 Mar 6;22(9):1358-64), and a 13-year-old male diagnosed with 3 simultaneous extra-adrenal PGLs whose tumor showed loss of heterozygosity (LOH) at the SDHB locus (Prasad P et al. Cancer Genet Cytogenet. 2009;192(2):82-85). This mutation has also been reported in an individual diagnosed with bilateral renal carcinoma at age 27. His unaffected mother was also a carrier and there was no known family history of PGL/PCC (Paik, JY et al. J Clin Oncol. 2014 Feb 20;32(6):e10-3). 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 when compared to wildtype, indicating nonsense-mediated mRNA decay or protein degradation as a mechanism for absent enzymatic activity (Kim E, Endocr. Relat. Cancer 2015 Jun; 22(3):387-97)<span style="background-color:initial">. In addition to the clinical and functional data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001058703 SCV001223294 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2019-12-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln30Argfs*47) in the SDHB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs747198089, ExAC 0.002%). This variant has been observed in individuals affected with clinical features of hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndrome (PMID: 12618761, 24395865, 19596260). ClinVar contains an entry for this variant (Variation ID: 186518). Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). For these reasons, this variant has been classified as Pathogenic.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505352 SCV000599485 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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