ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.340G>A (p.Gly114Ser)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000707336 SCV000836428 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-02-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 114 of the VHL protein (p.Gly114Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 1 of the VHL coding sequence, which is part of the consensus splice site for this exon. 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 (VHL) syndrome, or VHL-associated lesions (PMID: 20660572, 23407287, 15002726, Invitae). This variant is also known as c.553G>A in the literature. Other missense substitutions at this codon (p.Gly114Arg and p.Gly114Cys) have been reported in individuals affected with VHL syndrome (PMID: 7728151, 27527340, 7987306). This suggests that the glycine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that while this missense change does not affect microtubule stabilization, it does exhibit disrupted microtubule turnover, reduced assembly of the VCB-Cul2 complex, and decreased HIF-1 alpha binding and ubiquitination (PMID: 11865071, 12510195, 20855504). For these reasons, this variant has been classified as Pathogenic.

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