ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.485G>T (p.Cys162Phe) (rs397516444)

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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 RCV000036548 SCV000697522 pathogenic Von Hippel-Lindau syndrome 2016-02-04 criteria provided, single submitter clinical testing Variant summary: This c.485G>T affects a conserved nucleotide, resulting in amino acid change from Cys to Phe in alfa domain of VHL protein. 4/4 in-silico tools predict this variant to be damaging. The residue p.Cys162 is reported to directly contact with elongins and functional assays show that this variant abrogates the binding to elongin/Cul2 (Ohh_1999, Ohh_2000, Hansen_2002). The variant was also shown to abrogate the ubiquitination and binding to HIF and binding to E-cadherin (Ohh_2000, Hansen_2002, Evans_2007). These findings prove that this variant is functionally defective. This variant was found in 1/121234 control chromosomes including the broad and large populations from ExAC at a frequency of 0.0000082, which is lower than the maximal expected frequency of a pathogenic allele (0.0000208). This variant has been found in at least six independent VHL patients/families. One clinical lab (via ClinVar) has classified this variant as pathogenic. Other likely pathogenic variants (namely, p.C162R, p.C162W, and p.C162Y. p.Cys162TrpfsX12, etc.) have also been reported at this p.C162 residue, suggesting that this codon is likely to be a mutational hot-spot. Taken together, this variant has been classified as a Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036548 SCV000060203 pathogenic Von Hippel-Lindau syndrome 2007-04-18 no assertion criteria provided clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000036548 SCV000264759 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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