ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.327C>G (p.Ile109Met)

dbSNP: rs863224371
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001338507 SCV001532174 uncertain significance Chuvash polycythemia; Von Hippel-Lindau syndrome 2023-02-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 109 of the VHL protein (p.Ile109Met). This variant is not present in population databases (gnomAD no frequency). 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: 1035620). 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. 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.
Ambry Genetics RCV002322272 SCV002606507 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-17 criteria provided, single submitter clinical testing The p.I109M variant (also known as c.327C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 327. The isoleucine at codon 109 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not 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 RCV004005152 SCV004838985 uncertain significance Von Hippel-Lindau syndrome 2024-01-03 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with methionine at codon 109 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 not been identified 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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