ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.287-2A>G (rs1064794270)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486186 SCV000568589 pathogenic not provided 2017-03-17 criteria provided, single submitter clinical testing The c.287-2A>G splice site variant in the SDHB gene has been previously reported in multiple individuals with paragangliomas (for examples, see Neumann et al., 2004; Burnichon et al., 2009). This variant destroys the canonical splice acceptor site in intron 3, and is expected to cause abnormal gene splicing. Furthermore, another variant at this splice site (c.287-1G>C) has been reported in association with paraganglioma and pheochromocytoma, supporting the functional importance of this region of the protein (Timmers et al., 2007). Based on currently available evidence, we consider c.287-2A>G to be pathogenic..
Ambry Genetics RCV000492665 SCV000581193 pathogenic Hereditary cancer-predisposing syndrome 2020-02-14 criteria provided, single submitter clinical testing The c.287-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 4 in the SDHB gene. This germline mutation was reported in one family diagnosed with paragangliomas (Burnichon N et al. J. Clin. Endocrinol. Metab., 2009 Aug;94:2817-27). In another study of 417 unrelated individuals, this mutation was identified in two German individuals (one female and one male) with nonfunctional head and neck paragangliomas diagnosed at ages 43 and 45, respectively; this mutation is described as SDHB c.421-2A>G in this paper (Neumann HP et al. JAMA, 2004 Aug;292:943-51). This mutation was also identified in a cohort of 1640 index patients diagnosed with paraganglioma or pheochromocytoma (Buffet A et al. Horm. Metab. Res., 2012 May;44:359-66). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000486186 SCV001249152 pathogenic not provided 2021-03-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001195795 SCV001366215 pathogenic Paragangliomas 4 2018-10-30 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3,PP5.
Invitae RCV001203212 SCV001374364 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2019-06-16 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 of the SDHB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals affected with pheochromocytoma and paraganglioma (PMID: 15328326, 19454582, 17200167, Invitae). ClinVar contains an entry for this variant (Variation ID: 420072). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000486186 SCV001446494 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing

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