ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.599G>A (p.Arg200Gln) (rs754016774)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479035 SCV000570808 uncertain significance not provided 2018-12-24 criteria provided, single submitter clinical testing This variant is denoted VHL c.599G>A at the cDNA level, p.Arg200Gln (R200Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has been identified in the heterozygous state in at least one individual with erythrocytosis (Oliveira 2015). VHL Arg200Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether VHL Arg200Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000823835 SCV000964706 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-09-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 200 of the VHL protein (p.Arg200Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs754016774, ExAC 0.01%). This variant has been observed in individual(s) with pheochromocytoma (PMID: 30877234). ClinVar contains an entry for this variant (Variation ID: 421558). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.Arg200 amino acid residue in VHL have been observed in individuals affected with autosomal recessive, familial erythrocytosis type 2 (PMID: 9058738, 11987242, 12415268, 19494350). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001024771 SCV001186850 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-24 criteria provided, single submitter clinical testing The p.R200Q variant (also known as c.599G>A), located in coding exon 3 of the VHL gene, results from a G to A substitution at nucleotide position 599. The arginine at codon 200 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been identified in a heterozygous state in a patient with erythrocytosis (Oliveira JL et al. Am. J. Hematol., 2018 May;:). A similar alteration affecting this same amino acid, p.R200W, is known to cause autosomal recessive Chuvash polycythemia, a condition characterized by increased red blood cell mass and high risk of peripheral thrombosis and cerebrovascular events (Ang SO et al. Nat. Genet. 2002 Dec;32:614-21; Liu E et al. Blood. 2004 Mar;103:1937-40; Gordeuk VR et al. Blood. 2004 May;103:3924-32; Tomasic NL et al. Haematologica. 2013 Apr;98(4):560-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV001143974 SCV001304548 likely benign Von Hippel-Lindau syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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