ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.416C>T (p.Ser139Phe)

dbSNP: rs587780732
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001317982 SCV001508666 likely pathogenic Chuvash polycythemia; Von Hippel-Lindau syndrome 2024-03-01 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 139 of the VHL protein (p.Ser139Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 25078357). ClinVar contains an entry for this variant (Variation ID: 216478). 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 with a positive predictive value of 95%. 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.
Baylor Genetics RCV003462331 SCV004208769 uncertain significance Chuvash polycythemia 2023-06-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV004020464 SCV005036463 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-20 criteria provided, single submitter clinical testing The p.S139F variant (also known as c.416C>T), located in coding exon 2 of the VHL gene, results from a C to T substitution at nucleotide position 416. The serine at codon 139 is replaced by phenylalanine, an amino acid with highly dissimilar 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.

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