ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409700 SCV000489077 uncertain significance Von Hippel-Lindau syndrome 2016-08-23 criteria provided, single submitter clinical testing
Invitae RCV000467198 SCV000553375 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-12-26 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. This variant is present in population databases (rs578091032, ExAC 0.6%). This variant has been observed in an individual affected with renal carcinoma (PMID: 31034483). 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, 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 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.
Ambry Genetics RCV000492595 SCV000580981 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Illumina Clinical Services Laboratory,Illumina RCV000409700 SCV001309436 uncertain significance Von Hippel-Lindau syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198695 SCV001369690 uncertain significance Micrognathia; Nystagmus; Abnormal facial shape; Bulbous nose; Strabismus; Abnormal electroretinogram; Abnormality of visual evoked potentials; Pectus carinatum; Scaphocephaly 2019-12-11 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PP5. This variant was detected in heterozygous state.
ITMI RCV000122260 SCV000086485 not provided not specified 2013-09-19 no assertion provided reference population

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