ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.268C>T (p.Arg90Ter) (rs74315366)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030621 SCV000053299 pathogenic Pheochromocytoma; Hereditary Paraganglioma-Pheochromocytoma Syndromes 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037718 SCV000061380 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 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 2019-07-05 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 a significant frequency in large population cohorts (Lek 2016); 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, 32741965)
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 2017-12-21 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. <span style="background-color:initial">This pathogenic mutation has been reported in multiple unrelated families exhibiting pheochromocytomas and/or paragangliomas (Astuti D et al. Am J Hum Genet<span style="background-color:initial">. 2001 Jul;69(1):49-54; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91:827-36​; <span style="background-color:initial">Ricketts<span style="background-color:initial"> CJ et al. J Urol<span style="background-color:initial">. 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<span style="background-color:initial">). 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). <span style="background-color:initial">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.
Invitae RCV000627749 SCV000554022 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-10-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 90 (p.Arg90*) of the SDHB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs74315366, ExAC 0.002%). This variant has been reported in the literature in individuals and families affected with pheochromocytoma, paraganglioma and renal cell carcinoma (PMID: 11404820, 23083876, 21348866, 24466223, 12618761, 163114641, 25326637, 16317055, 21934479, 19454582,18419787). This variant is also known as R91X in the literature. ClinVar contains an entry for this variant (Variation ID: 12778). Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). 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
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 Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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