ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.629G>A (p.Arg210Gln) (rs138780791)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115743 SCV000149652 uncertain significance not provided 2018-06-12 criteria provided, single submitter clinical testing This variant is denoted VHL c.629G>A at the cDNA level, p.Arg210Gln (R210Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant, also defined as VHL c.842G>A (p.Arg281Gln) using alternate nomenclature, was observed in the germline of a pediatric patient with a glioma (Zhang 2015). VHL Arg210Gln was observed at an allele frequency of 0.013% (3/23,970) in individuals of African ancestry in large population cohorts (Lek 2016). VHL Arg210Gln 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 Arg210Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000627744 SCV000153873 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 210 of the VHL protein (p.Arg210Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs138780791, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with a glioma (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 127828). 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.
Counsyl RCV000119153 SCV000488335 uncertain significance Von Hippel-Lindau syndrome 2016-03-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000492305 SCV000580977 likely benign Hereditary cancer-predisposing syndrome 2019-02-28 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign)
Illumina Clinical Services Laboratory,Illumina RCV000119153 SCV001306569 uncertain significance 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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