ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.166_170del (p.Pro56fs)

dbSNP: rs786202100
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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 RCV000164746 SCV000215418 pathogenic Hereditary cancer-predisposing syndrome 2022-10-26 criteria provided, single submitter clinical testing The c.166_170delCCTCA pathogenic mutation, located in coding exon 2 of the SDHB gene, results from a deletion of 5 nucleotides at nucleotide positions 166 to 170, causing a translational frameshift with a predicted alternate stop codon (p.P56Yfs*5). This well-described mutation has been identified in numerous individuals with various tumors across the SDHx spectrum, including pheochromocytoma, paraganglioma, gastrointestinal stromal tumor (GIST), and/or renal cell carcinoma (Neumann HP et al. JAMA 2004 Aug;292(8):943-51; Mora J et al. Pediatr. Blood Cancer 2006 Nov;47(6):785-9; Amar L et al. J. Clin. Endocrinol. Metab. 2007 Oct;92(10):3822-8; Persu A et al. J. Hypertens. 2008 Jul;26(7):1395-401; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Gill AJ et al. Am. J. Surg. Pathol. 2011 Oct;35(10):1578-85). Haplotype analysis suggests that the c.166_170delCCTCA alteration is enriched in the Spanish population due to a founder effect (Cascón A et al. J. Clin. Endocrinol. Metab. 2009 May;94(5):1701-5). This alteration was originally described as c.300-4delCCTCA in the literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000467539 SCV000553997 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2024-01-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Pro56Tyrfs*5) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with pheochromocytoma and/or paraganglioma (PMID: 15328326, 16304664, 17652212, 19258401, 21934479, 25130709). This variant is also known as 300-4delCCTCA or c.300_304delCCTCA. ClinVar contains an entry for this variant (Variation ID: 185342). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002472 SCV001160420 pathogenic not specified 2019-03-21 criteria provided, single submitter clinical testing The SDHB c.166_170delCCTCA; p.Pro56fs variant (rs786202100), also published as 300_304delCCTCA, is reported in the literature in numerous individuals affected with paraganglioma and/or pheochromocytoma (Amar 2007, Burnichon 2009, Cascon 2009, Gill 2011, Jove 2014, Mora 2006, Neumann 2004). This variant has been discussed as a founder mutation in affected individuals of Spanish descent (Cascon 2009). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by several laboratories in ClinVar (Variation ID: 185342). This variant causes a frameshift by deleting five nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Amar L et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007 Oct;92(10):3822-8. Burnichon N et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27. Cascon A et al. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab. 2009 May;94(5):1701-5. Gill AJ et al. Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol. 2011 Oct;35(10):1578-85. Jove et al. Simultaneous KIT mutation and succinate dehydrogenase (SDH) deficiency in a patient with a gastrointestinal stromal tumour and Carney-Stratakis syndrome: a case report. Histopathology. 2014 Nov;65(5):712-7. Mora J et al. Pediatric paraganglioma: an early manifestation of an adult disease secondary to germline mutations. Pediatr Blood Cancer. 2006 Nov;47(6):785-9. Neumann HP et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004 Aug 25;292(8):943-51.
Division of Medical Genetics, University of Washington RCV001257497 SCV001434314 pathogenic Paragangliomas 4 2019-10-29 criteria provided, single submitter clinical testing This variant has been reported in the literature in multiple individuals affected with pheochromocytoma and/or paraganglioma [Neumann 2004, Mora 2006, Amar 2007, Cascon 2009, Gill 2011, Jove 2014]. This variant leads to a translational frameshift and the introduction of a premature termination codon 5 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of SDHB is a well-established mechanism of disease for hereditary paraganglioma-pheochromocytoma syndrome [Burnichon 2009, Ricketts 2010]. This variant is not present in population databases (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PM2; PVS1
Baylor Genetics RCV001294007 SCV001482758 pathogenic Pheochromocytoma 2018-12-07 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 15328326, 21934479, 25130709, 28152038]
GeneDx RCV001753560 SCV002005666 pathogenic not provided 2023-02-07 criteria provided, single submitter clinical testing Frameshift 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 in large population cohorts (gnomAD); Also known as Pro28TyrfsX5; This variant is associated with the following publications: (PMID: 17652212, 25130709, 28152038, 30050099, 31216007, 21934479, 15328326, 31431315, 31092265, 30262796, 18551016, 28973655, 20208144, 18382370, 31492822, 24436918, 28529006, 31589614, 19258401, 33900943, 34313605)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001294007 SCV002074521 pathogenic Pheochromocytoma 2022-01-04 criteria provided, single submitter clinical testing Variant summary: SDHB c.166_170delCCTCA (p.Pro56TyrfsX5) 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, which are commonly known mechanisms for disease. This variant is also known as c.32_36delCCTCA in HGVS and 300-4delCCTCA in the literature. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251378 control chromosomes (gnomAD). c.166_170delCCTCA has been reported in the literature in multiple individuals affected with Paraganglioma and/or Pheochromocytoma (examples: Neumann_2004, Cascon_2009, Burnichon_2009, Andrews_2018 and Benn_2018). These data indicate that the variant is associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002498816 SCV002806235 pathogenic Gastrointestinal stromal tumor; Carney-Stratakis syndrome; Paragangliomas 4; Pheochromocytoma; Mitochondrial complex 2 deficiency, nuclear type 4 2022-04-10 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV001257497 SCV004018406 pathogenic Paragangliomas 4 2023-03-22 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics RCV003474863 SCV004203031 pathogenic Gastrointestinal stromal tumor 2024-02-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001753560 SCV005624020 pathogenic not provided 2024-05-21 criteria provided, single submitter clinical testing The SDHB c.166_170del (p.Pro56Tyrfs*5) variant alters the translational reading frame of the SDHB mRNA and causes the premature termination of SDHB protein synthesis. This variant has been reported in the published literature in individuals and families affected with PGL-PCC syndrome (PMIDs: 15328326 (2004), 21934479 (2011), 31431315 (2019)) and pituitary adenoma (PMID: 34313605 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

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