ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.154G>T (p.Glu52Ter) (rs373068386)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656989 SCV000211825 uncertain significance not provided 2018-09-07 criteria provided, single submitter clinical testing This variant is denoted VHL c.154G>T at the cDNA level and p.Glu52Ter (E52X) at the protein level. This variant is present in the primary VHL isoform pVHL30, and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. However, in the alternate clinically-relevant isoform pVHL19, this variant occurs upstream of the start codon and does not appear to affect the start codon or the Kozak translational consensus sequence of pVHL19. Multiple functional studies suggest that pVHl19 may be sufficient for VHL protein-protein interactions and tumor suppressor activity (Iliopoulos 1998, Schoenfeld 1998, Blankenship 1999). VHL Glu52Ter has been observed in at least one individual with CNS hemangioblastoma and an abnormal growth on the pancreas (Leonardi 2011); however, familial segregation information was not provided. Finally, internal data reveal carriers of this variant do not present with VHL. Based on currently available information, we consider VHL Glu52Ter to be a variant of uncertain significance.
Counsyl RCV000576421 SCV000677776 uncertain significance Von Hippel-Lindau syndrome 2017-05-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000161090 SCV000697481 uncertain significance not specified 2018-08-07 criteria provided, single submitter clinical testing Variant summary: VHL c.154G>T (p.Glu52X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Glu55fsX12, p.Gly57fsX75, p.Val62fsX5). The variant allele was found at a frequency of 4.1e-05 in 24438 control chromosomes. c.154G>T has been reported in the literature in an individual with haemangioblastoma of the central nervous system (Leonardi_2011) as well as other cancer phenotypes (Susswein_2015, Mandelker_2017). These data do not allow any conclusion about variant significance. A functional study showed the variant to undergoing proteasome-dependent degradation (Schoenfeld_2000). However, there is some evidence that a second transcript, in which the variant occurs upstream of the start codon, provides sufficient VHL protein-protein interactions and tumor suppressor activity (Iliopoulos_1998, Schoenfeld_1998). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS - possibly pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000161090 SCV000712524 uncertain significance not specified 2017-10-05 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign.
PreventionGenetics,PreventionGenetics RCV000656989 SCV000805322 uncertain significance not provided 2017-07-20 criteria provided, single submitter clinical testing
Invitae RCV000685691 SCV000813182 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the VHL gene (p.Glu52*). It is unclear whether it will result in an absent or disrupted protein product because a highly conserved, in-frame methionine located at codon 54 has the potential to rescue this truncating variant. This variant is present in population databases (rs373068386, ExAC 0.009%). This variant has been reported in individuals with breast cancer (PMID: 26681312), pancreatic cancer (PMID: 28454591), and erythrocytosis (PMID: 27651169). ClinVar contains an entry for this variant (Variation ID: 182982). Downstream of the known ATG start site, the nearest methionine codon that can be used to initiate translation of the VHL protein lies at codon 54. Several studies have shown that the VHL protein created from this downstream methionine is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722, 10102622). Based on these results, the impact of this variant on VHL protein function is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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