ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.544A>G (p.Arg182Gly) (rs778205243)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204757 SCV000261369 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 182 of the VHL protein (p.Arg182Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs778205243, ExAC 0.03%). This variant has been observed in an individual with clinical features of hereditary erythrocytosis (PMID: 29790589). 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. 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.
GeneDx RCV000235376 SCV000293307 uncertain significance not provided 2018-04-13 criteria provided, single submitter clinical testing This variant is denoted VHL c.544A>G at the cDNA level, p.Arg182Gly (R182G) at the protein level, and results in the change of an Arginine to a Glycine (AGG>GGG). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. VHL Arg182Gly was observed at an allele frequency of 0.01% (5/34418) in individuals of Latino ancestry in large population cohorts (Lek 2016). Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL Arg182Gly is located in the alpha domain (Yuen 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether VHL Arg182Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000663322 SCV000786593 uncertain significance Von Hippel-Lindau syndrome 2018-06-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000235376 SCV000805356 uncertain significance not provided 2018-03-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV001024120 SCV001186082 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-11 criteria provided, single submitter clinical testing Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV000663322 SCV001304547 likely benign Von Hippel-Lindau syndrome 2018-01-12 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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