Submissions for variant NM_000551.4(VHL):c.335A>G (p.Tyr112Cys)

dbSNP: rs869025633

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219736	SCV000274805	uncertain significance	Hereditary cancer-predisposing syndrome	2015-04-02	criteria provided, single submitter	clinical testing	The p.Y112C variant (also known as c.335A>G), located in coding exon 1 of the VHL gene, results from an A to G substitution at nucleotide position 335. The tyrosine at codon 112 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5609 samples (11218 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 4300 alleles tested) in our clinical cohort. This amino acid position is highly 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 p.Y112C remains unclear.
Invitae	RCV000631262	SCV000752290	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 112 of the VHL protein (p.Tyr112Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of von Hippel-Lindau syndrome type 2C (PMID: 26268347; Invitae). ClinVar contains an entry for this variant (Variation ID: 223189). 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 with a positive predictive value of 95%. This variant disrupts the p.Tyr112 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8956040, 10408776, 10823831, 19030229, 21204227). 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.
Athena Diagnostics	RCV001289414	SCV001477205	uncertain significance	not provided	2020-03-24	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV001289414	SCV002502811	likely pathogenic	not provided	2021-12-02	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208852	SCV000264711	uncertain significance	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing