ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.362A>G (p.Asp121Gly) (rs5030832)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000208830 SCV000697506 pathogenic Von Hippel-Lindau syndrome 2016-02-05 criteria provided, single submitter clinical testing Variant summary: c.362A>G affects a conserved nucleotide, resulting in amino acid change from Asp to Gly. 4/4 in-silico tools predict this variant to be damaging. This variant was not found in 121412 control chromosomes. This variant has been reported in multiple VHL patients. Functional studies showed that variant retained most of the proteins abilities, including its interaction with HIF in vitro and the downstream down-regulation of gene expression controlled by HIF, as well as supporting HIF-1 ubiquitination (less than that observed for wild-type pVHL), and the interaction with elongin C. (Hansen_2002, Ruiz-Llorente_2004). However, there is also study showed that only partial interaction with elongin C is retained and the recruiting a complex containing the essential human VBCE3 ubiquitin ligase components CHL2 and ROC1 is detected (Hacker _2008). Considering all these studies were performed in vitro, the disease mechanism of this variant remains unclear. Variants D121G, D121N both are listed as disease mutation in HGMD and have been reported in multiple publications suggesting the codon 121 might be a hotspot for mutations. Taken together, this variant was classified as a Pathogenic.
PreventionGenetics,PreventionGenetics RCV000679035 SCV000805342 pathogenic not provided 2017-08-16 criteria provided, single submitter clinical testing
Invitae RCV000801501 SCV000941278 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-06-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 121 of the VHL protein (p.Asp121Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with, or with clinical features of von Hippel-Lindau syndrome (PMID: 16572651, 7977367, 9681856, 15300849, 20660572, 11409863, 8956040). ClinVar contains an entry for this variant (Variation ID: 223200). Experimental studies have shown that this missense change affects nuclear export of the VHL protein and its effect on downstream target HIF (PMID: 17967880, 11865071, 21715564). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Asp121 amino acid residue in VHL. Other variants that disrupt this residue have been observed in affected individuals (PMID: 16142346, 25557216), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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 RCV000208830 SCV000264725 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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