Submissions for variant NM_000551.4(VHL):c.251T>C (p.Val84Ala)

dbSNP: rs1264207864

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000803042	SCV000942898	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 84 of the VHL protein (p.Val84Ala). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 648333). 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.Val84 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8592333, 16502427, 17688370, 21463266, 25078357). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics	RCV001015832	SCV001176711	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-15	criteria provided, single submitter	clinical testing	The p.V84A variant (also known as c.251T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 251. The valine at codon 84 is replaced by alanine, an amino acid with similar properties. 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 available evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV001772071	SCV002003118	uncertain significance	not provided	2020-02-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002487706	SCV002782715	uncertain significance	Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma	2021-11-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001658	SCV004818676	uncertain significance	Von Hippel-Lindau syndrome	2023-08-15	criteria provided, single submitter	clinical testing