ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.333C>G (p.Ser111Arg) (rs765978945)

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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 RCV000492675 SCV000580964 pathogenic Hereditary cancer-predisposing syndrome 2017-10-12 criteria provided, single submitter clinical testing The p.S111R pathogenic mutation (also known as c.333C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 333. The serine at codon 111 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals who meet established diagnostic criteria for Von Hippel-Lindau (VHL) syndrome (Chen F et al. Hum. Mutat. 1995 ; 5(1):66-75; Cybulski C et al. J. Med. Genet. 2002 Jul; 39(7):E38; Ambry internal data). Functional analysis indicates the serine at codon 111 is a critical phosphorylation residue, and is involved in regulation of cell cycle progression after DNA damage (Roe JS et al. Cell Cycle, 2011 Nov;10:3920-8). Based on internal structural assessment, this alteration targets a critical HIF-1 binding residue and impairs binding of the hydroxylated HIF-1<span style="font-family:dejavusans">&alpha; peptide (Hon WC et al. Nature, 2002 Jun;417:975-8; Min JH et al. Science, 2002 Jun;296:1886-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001204150 SCV001375343 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-06-16 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 111 of the VHL protein (p.Ser111Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in several individuals affected with von Hippel-Lindau syndrome (PMID: 7728151, 12114495, 25562111, 16868829). This variant is also known as c.546C>A in the literature. ClinVar contains an entry for this variant (Variation ID: 223187). This variant has been reported to affect VHL protein function (PMID: 22071692). 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. 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000208866 SCV000264709 likely pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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