ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.533T>C (p.Leu178Pro) (rs5030822)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492520 SCV000580952 likely pathogenic Hereditary cancer-predisposing syndrome 2017-03-09 criteria provided, single submitter clinical testing The p.L178P variant (also known as c.533T>C), located in coding exon 3 of the VHL gene, results from a T to C substitution at nucleotide position 533. The leucine at codon 178 is replaced by proline, an amino acid with some similar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with Von Hippel-Lindau syndrome (VHL) both with and without pheochromocytoma (Crossey PA et al. Hum. Mol. Genet. 1994 Aug3(8):1303-8; Erlic et al. Endocrine-Related Cancer. 2010. 17;875-883; Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67(6):758-62; Ong KR et al. Hum. Mutat. 2007 Feb;28(2):143-9; Zbar B et al. Hum. Mutat. 1996;8(4):348-57). This alteration has also been reported in individuals with personal history of pheochromocytoma or functional paraganglioma but without a formal diagnosis of VHL syndrome (Amar L et al. J. Clin. Oncol. 2005 Dec;23(34):8812-8). In the literature, this alteration has also been referred to as a common VHL germline mutation (Cybulski C et al. J. Med. Genet. 2002 Jul;39(7):E38; López-Guerrero JA et al. Adv Urol 2008:720840). Of note, this alteration is also designated as 746T>C in some published literature. Further, an alteration at the same location, p.L178Q (c.533T>A/746T>A), has been reported in an individual with personal and/or family history consistent with VHL (Glavac D et al. Hum. Genet. 1996 Sep;98(3):271-80). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000631291 SCV000752319 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2017-09-05 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 178 of the VHL protein (p.Leu178Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with von Hippel-Lindau disease in several families (PMID: 17024664, 19763184).  It has also been reported in several individual affected with von Hippel-Lindau disease (PMID: 27527340, 17024664, 19464396, 19763184). This variant is also known as 746T>C (p.L249P) in the literature. ClinVar contains an entry for this variant (Variation ID: 428795). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000767287 SCV000897845 pathogenic Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing

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