Submissions for variant NM_000551.4(VHL):c.149C>T (p.Ala50Val)

dbSNP: rs766576246

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481405	SCV000570302	uncertain significance	not provided	2016-05-12	criteria provided, single submitter	clinical testing	This variant is denoted VHL c.149C>T at the cDNA level, p.Ala50Val (A50V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. VHL Ala50Val was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. VHL Ala50Val occurs at a position that is not conserved and is not located in a known functional domain (Yuen 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether VHL Ala50Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071961	SCV001237300	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2021-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, a(n) neutral and non-polar amino acid, with valine, a(n) neutral and non-polar amino acid, at codon 50 of the VHL protein (p.Ala50Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 421185). 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 not expected to disrupt VHL protein function. 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	RCV002395163	SCV002701430	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-26	criteria provided, single submitter	clinical testing	The p.A50V variant (also known as c.149C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 149. The alanine at codon 50 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.