ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.86_87delinsTT (p.Gly29Val) (rs879254115)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235782 SCV000293551 uncertain significance not provided 2017-07-14 criteria provided, single submitter clinical testing This variant is denoted VHL c.86_87delGCinsTT at the cDNA level, p.Gly29Val (G29V) at the protein level. The surrounding sequence is GACG[delGC][insTT]GGGGA. This in frame deletion and insertion results in the missense change of a Glycine to a Valine (GGC>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Neither VHL c.86_87delGCinsTT nor VHL Gly29Val (by this or an alternate nucleotide change) was observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. VHL c.86_87delGCinsTT occurs at a position that is not conserved and is located within amino acid tandem repeat 4 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether VHL c.86_87delGCinsTT is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000533627 SCV000626919 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2017-07-06 criteria provided, single submitter clinical testing This variant, c.86_87delGCinsTT, is a complex sequence change that results in the replacement of a glycine with valine at codon 29 of the VHL protein (p.Gly29Val). The glycine residue is weakly conserved and there is a modearte physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 246132). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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