ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.203C>T (p.Ser68Leu)

dbSNP: rs869025617
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000767234 SCV000897777 uncertain significance Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV001046095 SCV001209983 likely pathogenic Chuvash polycythemia; Von Hippel-Lindau syndrome 2022-07-18 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 625222). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser68 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 10627136, 12000816, 17661816, 27785399), which suggests that this may be a clinically significant amino acid residue. 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. This missense change has been observed in individual(s) with clinical features of VHL (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 68 of the VHL protein (p.Ser68Leu).
Ambry Genetics RCV002422648 SCV002720273 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-13 criteria provided, single submitter clinical testing The p.S68L variant (also known as c.203C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 203. The serine at codon 68 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in an individual with a personal history of pheochromocytoma and paraganglioma (Ambry internal data). Another alteration at this same codon, p.S68P, has been reported in patients with VHL-associated features (Hes FJ et al. Clin Genet, 2007 Aug;72:122-9; Kinyas S et al. Balkan J Med Genet, 2015 Dec;18:65-70). 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.

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