ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.541-2A>G (rs786201161)

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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 RCV000162804 SCV000213285 pathogenic Hereditary cancer-predisposing syndrome 2019-04-28 criteria provided, single submitter clinical testing The c.541-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 6 in the SDHB gene. This mutation was detected in several individuals with personal and/or family history of pheochromocytoma, paraganglioma, and renal cell carcinoma (Timmers HJ et al. J Clin Endocrinol Metab. 2007;92(3):779-86. Ricketts CJ et al. J Urol. 2012 Dec;188(6):2063-71. Choat H, et al. Case Rep Endocrinol 2014 ; 2014:502734; Casey RT et al. J. Clin. Endocrinol. Metab., 2017 11;102:4013-4022; Huang Y et al. Endocr Connect, 2018 Dec;7:1217-1225). 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.
Illumina Clinical Services Laboratory,Illumina RCV000374774 SCV000351417 likely pathogenic SDHB-Related Disorders 2016-06-14 criteria provided, single submitter clinical testing The c.541-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in three studies in which it is found in a total of four hereditary paraganglioma-pheochromocytoma syndrome patients, all in a heterozygous state (Timmers et al. 2007; Ricketts et al. 2012; Choat et al. 2014). The variant was absent from an unaffected brother of one of the patients (Choat et al. 2014). Control data are unavailable for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Based on the evidence and the potential impact of splice acceptor variants, the c.541-2A>G variant is classified as likely pathogenic for SDHB-related disorders.
GeneDx RCV000523104 SCV000616872 pathogenic not provided 2015-04-03 criteria provided, single submitter clinical testing The c.541-2 A>G splice site variant in the SDHB gene has been previously reported in association with an SDHB-related disorder (Timmers et al., 2007). This variant destroys the canonical splice acceptor site in intron 5, and is expected to cause abnormal gene splicing.
Invitae RCV000797086 SCV000936626 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-08-06 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 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). This variant has been observed in individuals affected with paragangliomas and pheochromocytomas (PMID: 17200167, 25298897, 23083876) and in an individual affected with leukodystrophic encephalopathy (PMID: 26642834). This variant is also known as IVS5–2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 183925). 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.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505364 SCV000599511 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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