ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.463+3A>G (rs1131690954)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492736 SCV000580956 pathogenic Hereditary cancer-predisposing syndrome 2019-04-04 criteria provided, single submitter clinical testing The c.463+3A>G intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 2 in the VHL gene. This intronic alteration (designated as IVS2+3A>G), was reported in an 18-year-old female with bilateral pheochromocytomas and a pancreatic neuroendocrine tumor. Her family history included CNS tumors, hemangioblastomas, and adrenal tumors (Boaz RJ et al. Indian J. Endocrinol. Metab. 2011 Oct;15 Suppl 4:S402-5; Ebenazer A et al. Fam. Cancer. 2013 Sep;12(3):519-24). It was confirmed to be de novo in a patient with a history of pheochromocytoma, pancreatic neuroendocrine tumor, and CNS hemangioblastomas (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587888 SCV000697516 uncertain significance not provided 2016-04-12 criteria provided, single submitter clinical testing Variant summary: The variant of interest is located at a conserved intronic position with 3/5 in silico programs via Alamut predicting an effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in affected individuals via publications. However, no reputable databases and/or clinical laboratories cite the variant. Although, another variant at this position, c.463+3A>T has been reported in affected individuals via publications. Therefore, taking all lines of evidence into consideration, the variant of interest is classified as VUS-possibly pathogenic until additional information becomes available.

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