ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.3G>T (p.Met1Ile) (rs578091032)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000562501 SCV000675801 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000411808 SCV000488346 uncertain significance Von Hippel-Lindau syndrome 2016-03-08 criteria provided, single submitter clinical testing
GeneDx RCV000236708 SCV000293412 uncertain significance not provided 2018-08-02 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. VHL c.3G>T has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was observed at an allele frequency of 0.02% (3/17,842) in individuals of Finnish ancestry in large population cohorts (Lek 2016). Functional analysis has identified the presence of two VHL gene products from two ATG start sites; therefore, it is possible that the alternate ATG may be used, resulting in a functional protein product (Iliopoulos 1998, Blankenship 1999). Based on currently available evidence, it is unclear whether VHL c.3G>T is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000228663 SCV000285495 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-10-04 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the VHL mRNA. While this variant is present in population databases (rs578091032), the frequency information is unreliable, as metrics indicate low coverage at this position in the ExAC database. This variant has not been reported in the literature in an individual with VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 238106). 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).  Knock-in mice with this VHL isoform were found to be phenotypically similar to wild-type mice, although on a cellular level, microtubule activity was shown to be altered (PMID: 23541568).  Based on these results, the impact of this variant on VHL protein function is uncertain. For these reasons, this change has been classified as a Variant of Uncertain Significance.
PreventionGenetics RCV000236708 SCV000805345 uncertain significance not provided 2018-03-14 criteria provided, single submitter clinical testing

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