ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.166_170del (p.Pro56fs) (rs786202100)

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Total submissions: 5
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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 2019-01-08 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). <span style="background-color:initial">Haplotype <span style="background-color:initial">analysis suggests that the c.166_170delCCTCA alteration is enriched in the Spanish population due to a founder effect (<span style="background-color:initial">Casc&oacute;n A et al. J. Clin. Endocrinol. Metab. 2009 May;94(5):1701-5<span style="background-color:initial">). This alteration was originally described as c.300-4delCCTCA in the literature. 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 RCV000467539 SCV000553997 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-09-23 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with pheochromocytoma and/or paraganglioma (PMID: 15328326, 19258401, 16304664, 17652212), with or without gastrointestinal stromal tumors (PMID: 25130709) or renal tumors (PMID: 21934479). This variant is also known as 300-4delCCTCA or c.300_304delCCTCA in the literature. ClinVar contains an entry for this variant (Variation ID: 185342). Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). 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 ( 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]

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