ClinVar Miner

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

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Total submissions: 2
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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 2018-12-19 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 not been reported in the literature in individuals with VHL-related disease. 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.

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