ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.1A>T (p.Met1Leu) (rs1060503557)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000458939 SCV000553394 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-12-12 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the VHL mRNA. The next in-frame methionine is located at codon 54. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been reported in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 411967). 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). 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.
GeneDx RCV000579235 SCV000680941 uncertain significance not provided 2017-04-03 criteria provided, single submitter clinical testing This variant alters the initiator Methionine codon, and the resultant protein would be described as ?p.Met1?? to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. Functional studies have identified the presence of an alternate translation start site at codon 54 that produces a stable VHL protein product, pVHL19, that is able to carry out tumor suppression and other activities of the full-length VHL protein, but differs with respect to subcellular localization and ability to bind p14ARF (Iliopoulos 1998, Blankenship 1999, Minervini 2015). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Based on currently available evidence, it is unclear whether VHL c.1A>T is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000663055 SCV000786106 uncertain significance Von Hippel-Lindau syndrome 2018-03-01 criteria provided, single submitter clinical testing

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