ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.545G>A (p.Arg182Lys) (rs749774529)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214081 SCV000275848 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-05 criteria provided, single submitter clinical testing The p.R182K variant (also known as c.545G>A), located in coding exon 3 of the VHL gene, results from a G to A substitution at nucleotide position 545. The arginine at codon 182 is replaced by lysine, an amino acid with highly 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.
Invitae RCV000704890 SCV000833862 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-10-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 182 of the VHL protein (p.Arg182Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs749774529, ExAC 0.01%). This variant has not been reported in the literature in individuals with VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 231869). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance 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.
Johns Hopkins Genomics, Johns Hopkins University RCV001543676 SCV001762366 uncertain significance Von Hippel-Lindau syndrome 2021-07-06 criteria provided, single submitter clinical testing VHL c.545G>A (rs749774529) is rare (<0.1%) in a large population dataset (gnomAD: 2/251430 total alleles; 0.0008%; no homozygotes) and has been reported in ClinVar (Variation ID: 231869). This variant has not been reported as a germline change in the literature, to our knowledge. Of two bioinformatics tools queried, two predicts that the substitution would be possibly damaging, while one predicts that it would be tolerated. The arginine residue at this position is evolutionarily conserved across the mammalian species assessed We consider the clinical significance of VHL c.545G>A to be uncertain at this time.
GeneDx RCV001570193 SCV001794433 uncertain significance not provided 2019-10-22 no assertion criteria provided clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 20151405, 23070752, 26228213, 14965365)

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