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 2019-06-27 criteria provided, single submitter clinical testing The p.V194G variant (also known as c.581T>G), located in coding exon 3 of the VHL gene, results from a T to G substitution at nucleotide position 581. The valine at codon 194 is replaced by glycine, an amino acid with dissimilar properties. This alteration was first reported in a 17 year-old female patient presenting with malignant pheochromocytoma. Tissue analyses conducted on three distinct tumors from this patient all demonstrated loss of heterozygosity. This alteration was also detected in this patient's father, who was reported to be unaffected at the time of the study (Kawashima S et al. Endocr Pract. 2014 Jun;20(6):e96-e101). This alteration was found to segregate with disease in a family with clinical history suggestive of VHL (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. <span style="color:rgb(54, 43, 54); font-family:arial,sans-serif">Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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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