ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.241C>G (p.Pro81Ala)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001379600 SCV001577427 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-09-19 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 81 of the VHL protein (p.Pro81Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with erythrocytosis (PMID: 24115288). 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 variant disrupts the p.Pro81 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21389259, 27730413, 24134185, 22241717, 17102082, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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