ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.182C>T (p.Pro61Leu)

gnomAD frequency: 0.00001  dbSNP: rs746582207
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000560166 SCV000626884 uncertain significance Chuvash polycythemia; Von Hippel-Lindau syndrome 2023-08-11 criteria provided, single submitter clinical testing 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. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 61 of the VHL protein (p.Pro61Leu). This variant is present in population databases (rs746582207, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 456574). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function.
Ambry Genetics RCV000573623 SCV000675829 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-03 criteria provided, single submitter clinical testing The p.P61L variant (also known as c.182C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 182. The proline at codon 61 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV004003774 SCV004830537 uncertain significance Von Hippel-Lindau syndrome 2023-04-03 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 61 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with VHL-related disorders in the literature. This variant has been identified in 2/213718 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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