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
Integrated Genetics/Laboratory Corporation of America 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 2018-07-23 criteria provided, single submitter clinical testing This variant is denoted SDHB c.268C>T at the cDNA level and p.Arg90Ter (R90X) 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 many individuals with a personal and/or family history of paraganglioma, pheochromocytoma, gastrointestinal stromal tumor, and/or renal cell carcinoma, with several tumors showing absence of SDHB by immunohistochemistry (Astuti 2001, van Nederveen 2009, Gill 2011, Ricketts 2012, Elston 2017, Jochmanova 2017). We consider this variant to be pathogenic.
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 Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s)
Invitae RCV000627749 SCV000554022 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2019-12-13 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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