ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.581T>G (p.Val194Gly) (rs1131690963)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492180 SCV000580988 likely pathogenic Hereditary cancer-predisposing syndrome 2015-09-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Invitae RCV000547627 SCV000626912 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-01-26 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 194 of the VHL protein (p.Val194Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a young individual affected with adrenal and extra-adrenal pheochromocytomas, as well as a metastatic lung lesion. In all three tumors, there was loss-of-heterozygosity of the wild-type VHL allele (PMID: 24518179). ClinVar contains an entry for this variant (Variation ID: 428810). 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 disruptive, 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.

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