ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.335A>G (p.Tyr112Cys) (rs869025633)

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Total submissions: 3
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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 Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000631262 SCV000752290 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-04-09 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 112 of the VHL protein (p.Tyr112Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with clinical features of von Hippel-Lindau syndrome type 2C (PMID: 26268347, Invitae). ClinVar contains an entry for this variant (Variation ID: 223189). 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.Tyr112 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21204227, 8956040, 10408776, 10823831, 19030229). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000208852 SCV000264711 uncertain significance Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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