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 Lines of evidence used in support of classification: 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)
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
Invitae RCV000631262 SCV000752290 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2017-10-02 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 reported in an individual affected with von Hippel-Lindau syndrome (PMID: 26268347). 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. A different missense substitution at this codon (p.Tyr112His) has been determined to be likely pathogenic (PMID:  21204227, 8956040, 10408776, 10823831, 19030229). This suggests that the tyrosine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. 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.

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