ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.5C>G (p.Pro2Arg)

dbSNP: rs111246617
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000460146 SCV000553409 uncertain significance Chuvash polycythemia; Von Hippel-Lindau syndrome 2023-12-15 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2 of the VHL protein (p.Pro2Arg). This variant is present in population databases (no rsID available, gnomAD 0.005%). 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: 411980). 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 not expected to disrupt VHL protein function with a negative predictive value of 95%. 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.
Sema4, Sema4 RCV002256271 SCV002534193 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-25 criteria provided, single submitter curation
Ambry Genetics RCV002256271 SCV002657164 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-08 criteria provided, single submitter clinical testing The p.P2R variant (also known as c.5C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 5. The proline at codon 2 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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 RCV004001989 SCV004834225 uncertain significance Von Hippel-Lindau syndrome 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces proline with arginine at codon 2 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 2/139824 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.
Baylor Genetics RCV004568087 SCV005055819 uncertain significance Chuvash polycythemia 2023-11-04 criteria provided, single submitter clinical testing

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