ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.293A>C (p.Tyr98Ser) (rs864321643)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001064921 SCV001229857 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-02-04 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with serine at codon 98 of the VHL protein (p.Tyr98Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with von Hippel-Lindau (VHL) syndrome and to segregate in an affected family (PMID: 27539324, 29124493, 28388566). ClinVar contains an entry for this variant (Variation ID: 219160). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Tyr98 amino acid residue in VHL. Another variant that disrupts this residue has been observed in individuals with VHL-related conditions (PMID: 7759077, 7728151, 10408776, 21204227, 19763184, 19336503, 11483638), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as 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

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