ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.467A>G (p.Tyr156Cys) (rs397516441)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487045 SCV000568595 pathogenic not provided 2017-06-28 criteria provided, single submitter clinical testing This variant is denoted VHL c.467A>G at the cDNA level, p.Tyr156Cys (Y156C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant was observed in multiple individuals with pheochromocytoma (PCC) and/or paraganglioma (PGL), in both the sporadic and familial setting, several of whom had early-onset and/or bilateral disease (Neumann 2002, Bauters 2003, Gimenez-Roqueplo 2003, Amar 2005, Boedeker 2009, Gergics 2009, Pigny 2009, van Nederveen 2009, Van Slycke 2009, Nordstrom-O?Brien 2010, Kruizinga 2014, de Cubas 2015). This variant has also been observed in individuals with other features of von Hippel-Lindau syndrome (Olschwang 1998, Dollfus 2002, Erlic 2010). Favier et al. (2009) showed that PGL/PCC from carriers of VHL Tyr156Cys had an increase in lactate dehydrogenase activity compared to non-VHL PCC/PGL, and lacked expression of p53, which is stabilized and activated by the VHL protein, and TIGAR (TP53-induced glycolysis and apoptosis regulator) by immunohistochemistry. VHL Tyr156Cys was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL Tyr156Cys occurs at a position that is conserved in mammals and is located in the elongin C binding/alpha-domain (Yuen 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available evidence, we consider VHL Tyr156Cys to be pathogenic.
Ambry Genetics RCV000492752 SCV000580993 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-07 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Integrated Genetics/Laboratory Corporation of America RCV000036543 SCV000697518 pathogenic Von Hippel-Lindau syndrome 2016-02-03 criteria provided, single submitter clinical testing
Invitae RCV000631280 SCV000752308 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-07-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 156 of the VHL protein (p.Tyr156Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with pheochromocytoma and/or paraganglioma, likely representing von Hippel-Lindau syndrome type 2C (PMID: 12000816, 19336503, 19029228, 20151405, 16314641). ClinVar contains an entry for this variant (Variation ID: 43600). An experimental study has shown that patient-derived tumors carrying this variant increases glycolysis, leading to the Warburg effect (PMID: 19763184). The clinical significance of this finding is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036543 SCV000060198 pathogenic Von Hippel-Lindau syndrome 2008-08-13 no assertion criteria provided clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000036543 SCV000264751 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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