ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.563T>C (p.Leu188Pro)

dbSNP: rs1559429824
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Total submissions: 2
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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 RCV000767294 SCV000897852 likely pathogenic Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002536595 SCV003525022 pathogenic Chuvash polycythemia; Von Hippel-Lindau syndrome 2022-02-25 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 188 of the VHL protein (p.Leu188Pro). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 9829911, 15300849; Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu188 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7563486, 7987306, 8772572, 12844285, 15642680, 23772956). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 625266). This variant is also known as c.776T>C.

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