ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.593T>A (p.Leu198Gln)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001377066 SCV001574298 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-07-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with glutamine at codon 198 of the VHL protein (p.Leu198Gln). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of VHL-related conditions (PMID: 12000816, 20660572). 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.Leu198 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24555745, 27539324, 29124493). 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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