Submissions for variant NM_000551.4(VHL):c.250G>A (p.Val84Met)

dbSNP: rs5030827

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492467	SCV000580992	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-12-16	criteria provided, single submitter	clinical testing	The p.V84M variant (also known as c.250G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 250. The valine at codon 84 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in an individual affected with bilateral pheochromocytoma diagnosed at ages 1 year and 4 years; of note, this individual's father was also diagnosed with pheochromocytoma at age 40; however, genetic testing was not performed on the father (Stanojevic BR et al. Neoplasma. 2007;54:402-6). It was also identified in a patient diagnosed with a pheochromocytoma at age 8, with recurrence of disease at age 26 (Eisenhofer G et al. Horm. Metab. Res. 2012 May;44(5):343-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000631269	SCV000752297	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 84 of the VHL protein (p.Val84Met). This variant is present in population databases (no rsID available, gnomAD 0.001%). This missense change has been observed in individuals with clinical features of von Hippel-Lindau syndrome (PMID: 17688370; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 428813). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 17906660). This variant disrupts the p.Val84 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8592333, 11331612, 16502427, 25078357). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000767245	SCV000897789	uncertain significance	Von Hippel-Lindau syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000767245	SCV002051804	likely pathogenic	Von Hippel-Lindau syndrome	2021-10-20	criteria provided, single submitter	clinical testing