Submissions for variant NM_000551.4(VHL):c.290C>T (p.Pro97Leu)

dbSNP: rs2125125249

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002022744	SCV002292269	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-03-26	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 von Hippel-Lindau syndrome, clinical features of erythrocytosis and/or pheochromocytoma (PMID: 15300849, 16314641, 19763184, 29790589). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 97 of the VHL protein (p.Pro97Leu).
Ambry Genetics	RCV002441194	SCV002751915	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-16	criteria provided, single submitter	clinical testing	The p.P97L variant (also known as c.290C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 290. The proline at codon 97 is replaced by leucine, an amino acid with similar properties. In one study, this alteration was identified in a 17-year-old female who had pheochromocytoma and a brother with bilateral pheochromocytoma (Favier J et al. PLoS One, 2009 Sep;4:e7094). Additionally, this variant was identified in a 12-year-old male and a 10-year-old female who both had pheochromocytoma (Ben Aim L et al. J Med Genet, 2019 Aug;56:513-520). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004011117	SCV004830388	uncertain significance	Von Hippel-Lindau syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 97 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two families affected with VHL and in an individual affected with pheochromocytoma (PMID: 15300849, 16314641, 19763184). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.