ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.484T>C (p.Cys162Arg) (rs1553620313)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000587033 SCV000697521 pathogenic Von Hippel-Lindau syndrome 2016-08-31 criteria provided, single submitter clinical testing Variant summary: The c.484C>T (p.Cys162Arg) in VHL gene is a missense change that involves a non-conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant of interest is located within the elongin binding domain, and mutations in this region have been found in multiple VHL patients. The variant is absent from the control population dataset of ExAC but has been reported in multiple affected individuals from VHL families and was proven to segregate with the disease. In addition, codon Cy162 appears to be a hotspot, since other alterations of this codon, p.C162W, p.C162Y and p.C162F, were found in multiple VHL pts. Taking together, the variant was classified as Pathogenic.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000587033 SCV000897833 pathogenic Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV001060967 SCV001225689 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-02-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 162 of the VHL protein (p.Cys162Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with von Hippel-Lindau syndrome (PMID: 7728151, 8634692, 8641976, 9681856, 8956040). This variant is also known as c.697T>C (p.Cys233Arg) in the literature. ClinVar contains an entry for this variant (Variation ID: 496067). Experimental studies have shown that this missense change impairs Elongin C binding and results in reduced apoptosis when compared to wild-type VHL protein (PMID: 28052007). A different missense substitution at this codon (p.Cys162Trp) has been determined to be pathogenic (PMID: 17350623, 19270817, 9829912, 25867206, Invitae). This suggests that the cysteine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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