Submissions for variant NM_000551.4(VHL):c.463+3A>G

dbSNP: rs1131690954

Total submissions: 6

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.
3billion	RCV001809448	SCV002058542	uncertain significance	Pheochromocytoma	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been reported to be associated with VHL related disorder (ClinVar ID: VCV000428796).It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Myriad Genetics, Inc.	RCV003316644	SCV004018088	likely pathogenic	Von Hippel-Lindau syndrome	2023-03-10	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22145147, 22438210]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000587888	SCV001927631	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587888	SCV001973440	pathogenic	not provided		no assertion criteria provided	clinical testing