ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.3G>A (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 RCV000492595 SCV000580981 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000409700 SCV000489077 uncertain significance Von Hippel-Lindau syndrome 2016-08-23 criteria provided, single submitter clinical testing
GeneDx RCV000657025 SCV000566718 uncertain significance not provided 2018-11-05 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. This variant was identified in 1/43 healthy African individuals undergoing whole genome sequencing (Bodian 2014) and was observed at an allele frequency of 0.04% (6/15202) in individuals of African ancestry in large population cohorts (Lek 2016). Of note, the participants in the study by Bodian et al. were younger than 50 years old thus the unaffected status of this individual may not be significant. 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, Minervini 2017). Based on currently available information, it is unclear whether VHL c.3G>A is pathogenic or benign. We consider it to be a variant of uncertain significance.
ITMI RCV000122260 SCV000086485 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000467198 SCV000553375 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-10-15 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 poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 135406). 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). Based on these results, the impact of this variant on VHL protein function is uncertain. In summary, this variant has uncertain impact on VHL function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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