ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.486C>G (p.Cys162Trp) (rs5030622)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226031 SCV000285499 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 162 of the VHL protein (p.Cys162Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with von Hippel-Lindau disease (PMID: 9829912, 12202531, 19270817, 25867206) and renal cell carcinoma (PMID: 10408776, 15177666). Currently there is insufficient evidence to conclude whether this variant segregates with disease or not. This variant is also known in the literature as c.699C>G (p.Cys233Trp). ClinVar contains an entry for this variant (Variation ID: 223227). One experimental study has shown that this missense change disrupts the VHL-dependent proteasomal degradation failing to induce ubiquination of targeted proteins (PMID: 17350623). This variant disrupts the p.Cys162 amino acid residue in VHL. Other variant that disrupt this residue have been observed in affected individuals (PMID: 11331612), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000567560 SCV000664755 pathogenic Hereditary cancer-predisposing syndrome 2017-09-05 criteria provided, single submitter clinical testing The p.C162W pathogenic mutation (also known as c.486C>G), located in coding exon 3 of the VHL gene, results from a C to G substitution at nucleotide position 486. The cysteine at codon 162 is replaced by tryptophan, an amino acid with highly dissimilar properties. This pathogenic mutation has been reported in multiple individuals with personal and/or family history consistent with von Hippel-Lindau disease (Chen F et al. Hum. Mutat., 1995;5:66-75; Glavac D et al. Hum. Genet., 1996 Sep;98:271-80; Olschwang S et al. Hum. Mutat., 1998;12:424-30; Stolle C et al. Hum. Mutat., 1998;12:417-23; Gallou C et al. Hum. Mutat., 1999;13:464-75; Gläsker S et al. J. Neurol. Neurosurg. Psychiatr., 1999 Dec;67:758-62; Dollfus H et al. Invest. Ophthalmol. Vis. Sci., 2002 Sep;43:3067-74; Cho HJ et al. J. Korean Med. Sci., 2009 Feb;24:77-83; Wong M et al. Chin J Cancer, 2016 Aug;35:79). Further, one study has shown that this pathogenic mutation stabilized a variant of protein kinase C that suppresses epithelial cell polarization to the levels seen in the presence of a proteasome inhibitor suggesting this alteration results in a dominant-negative effect (Iturrioz X et al. FEBS Lett., 2007 Apr;581:1397-402). In addition, at least two other missense pathogenic mutations have been reported at this location including p.C162F (c.485G>T) and p.C162R (c.484T>C) (Hoffman MA et al. Hum. Mol. Genet., 2001 May;10:1019-27; Wong M et al. Chin J Cancer, 2016 Aug;35:79). Based on the available evidence, p.C162W is classified as a pathogenic mutation.
PreventionGenetics,PreventionGenetics RCV000679043 SCV000805353 uncertain significance not provided 2016-10-27 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000208792 SCV000264761 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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