Submissions for variant NM_000551.4(VHL):c.293A>C (p.Tyr98Ser)

dbSNP: rs864321643

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001064921	SCV001229857	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-10-17	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 219160). This missense change has been observed in individuals with von Hippel-Lindau (VHL) syndrome (PMID: 27539324, 28388566, 29124493). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 98 of the VHL protein (p.Tyr98Ser). This variant disrupts the p.Tyr98 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 7759077, 10408776, 11483638, 19336503, 19763184, 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.
Ambry Genetics	RCV002433899	SCV002747814	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-16	criteria provided, single submitter	clinical testing	The p.Y98S variant (also known as c.293A>C), located in coding exon 1 of the VHL gene, results from an A to C substitution at nucleotide position 293. The tyrosine at codon 98 is replaced by serine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals with a clinical diagnosis of VHL (Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23; Peng S et al. Oncotarget. 2017 Jun;8:38456-38465). This alteration has also been identified in individual with paragangliomas and/or pheochromocytomas (Khadilkar K et al. J Pediatr Endocrinol Metab, 2017 May;30:575-581; Lomte N et al. Fam Cancer, 2018 07;17:441-449). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Endocrinology Clinic, Seth G.S. Medical College	RCV000203508	SCV000258643	likely pathogenic	Pheochromocytoma	2015-12-01	no assertion criteria provided	research
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208847	SCV000264697	uncertain significance	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing