ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.640C>T (p.Gln214Ter)

dbSNP: rs876658461
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Total submissions: 11
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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 2022-07-27 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 2023-01-05 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 230243). This premature translational stop signal has been observed in individual(s) with pheochromocytoma and paraganglioma (PMID: 17943698, 19694205). This variant is not present in population databases (gnomAD no frequency). 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. Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898).
GeneDx RCV000657586 SCV000779323 pathogenic not provided 2023-02-27 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19694205, 25525159, 17943698, 28873162, 30787465)
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 pheochromocytoma-paraganglioma 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.
3billion RCV000238597 SCV002059106 pathogenic Paragangliomas 4 2022-01-03 criteria provided, single submitter clinical testing Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000230243, PMID:17943698). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Myriad Genetics, Inc. RCV000238597 SCV004018201 pathogenic Paragangliomas 4 2023-03-15 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics RCV003475004 SCV004203038 likely pathogenic Gastrointestinal stromal tumor 2022-06-05 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV001175589 SCV004821939 pathogenic Hereditary pheochromocytoma-paraganglioma 2023-11-02 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 6 of the SDHB gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with hereditary paranganglioma-pheochromocytoma syndrome (PMID: 17943698, 19694205, 32460727, 34654328). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHB function is a known mechanism of disease ( Based on the available evidence, this variant is classified as Pathogenic.

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