ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.235C>T (p.Arg79Cys) (rs200885420)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231302 SCV000285492 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-12-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 79 of the VHL protein (p.Arg79Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. The frequency data for this variant (rs200885420) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported in a compound heterozygous state in an individual affected with congenital polycythemia (PMID: 15642680). ClinVar contains an entry for this variant (Variation ID: 161400). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000235492 SCV000293496 uncertain significance not provided 2018-04-25 criteria provided, single submitter clinical testing This variant is denoted VHL c.235C>T at the cDNA level, p.Arg79Cys (R79C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been reported in the compound heterozygous state in an individual with congenital polycythemia (Bento 2005). VHL Arg79Cys was observed at an allele frequency of 0.04% (4/9,492) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located within an area on the surface of the beta-domain involved in binding with the ODD of HIF-alpha subunits (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 Arg79Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000412420 SCV000488813 uncertain significance Von Hippel-Lindau syndrome 2016-06-24 criteria provided, single submitter clinical testing
Mendelics RCV000412420 SCV001136310 benign Von Hippel-Lindau syndrome 2019-05-28 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148920 SCV000190676 likely benign Polycythemia (disease) 2014-06-01 no assertion criteria provided research

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