ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.278_279delinsTT (p.Gly93Val) (rs1559426072)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000707314 SCV000836405 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-02-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 93 of the VHL protein (p.Gly93Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This particular variant has not been reported in the literature in individuals with VHL-related disease. However, a different nucleotide change (c.278G>T, reported as c.491G>T) that causes the same amino acid substitution, has been reported in individuals affected with von Hippel-Lindau syndrome (PMID: 10095351, 12000816). 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"). A different missense substitution at this codon (p.Gly93Ser) has been determined to be pathogenic (PMID: 11409863, 12000816, 8707293, 22136840, 17922902). This suggests that the glycine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. 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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