ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.640C>T (p.Gln214Ter) (rs876658461)

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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 RCV000215175 SCV000273710 pathogenic Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing The p.Q214* pathogenic mutation (also known as c.640C>T) located in coding exon 6 of the SDHB gene, results from a C to T substitution at nucleotide position 640. This changes the amino acid from a glutamine to a stop codon within coding exon 6. This mutation was first described in a 40-year-old Chinese female with a recurrent pheochromocytoma in the left adrenal gland. The patient's first pheochromocytoma had been removed 18 years prior to this study (Reusch J et al. Exp Clin Endocrinol Diabetes. 2007;115(9):616-8). It was also identified in a 15 year-old female with hypertension due to a functional abdominal paraganglioma (Kim MS et al. J. Pediatr. Endocrinol. Metab. 2009 Jun; 22(6):565-71). 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000238597 SCV000297132 pathogenic Paragangliomas 4 2015-10-13 criteria provided, single submitter clinical testing
Invitae RCV000472972 SCV000554012 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-04-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln214*) in the SDHB gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with pheochromocytoma and paraganglioma (PMID: 17943698, 19694205). ClinVar contains an entry for this variant (Variation ID: 230243). 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 RCV000657586 SCV000779323 pathogenic not provided 2018-07-18 criteria provided, single submitter clinical testing This variant is denoted SDHB c.640C>T at the cDNA level and p.Gln214Ter (Q214X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), 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 at least two individuals with early-onset paraganglioma and pheochromocytoma (Reusch 2007, Kim 2009) and is considered pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762866 SCV000893246 pathogenic Carney-Stratakis syndrome; Paragangliomas 4; Pheochromocytoma 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175589 SCV001339227 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2020-03-26 criteria provided, single submitter clinical testing Variant summary: SDHB c.640C>T (p.Gln214X) 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. The variant was absent in 251290 control chromosomes. c.640C>T has been reported in the literature in individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (Reusch_2007, Kim_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
New York Genome Center RCV000238597 SCV001480232 likely pathogenic Paragangliomas 4 2019-08-28 criteria provided, single submitter clinical testing The inherited c.640C>T (p.Gln214Ter) variant identified in the SDHB gene leads to the premature termination of the protein at amino acid 214/281 (coding exon 6/8) and is predicted to undergo nonsense mediated decay. This variant is absent from gnomAD and ExAC, suggesting it is not a common benign variant in the populations represented in these databases. This variant is classified as Pathogenic in ClinVar (VarID:230243), and has been reported in the literature in individuals with early onset Pheochromocytomas [PMID: 17943698; PMID: 19694205]. Given its deleterious nature, its absence in population databases, and its observation in affected individuals in the literature, the c.640C>T (p.Gln214Ter) variant identified in the SDHB gene is reported here as Likely Pathogenic.

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