ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.221T>C (p.Val74Ala) (rs5030803)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484327 SCV000571514 uncertain significance not provided 2016-08-29 criteria provided, single submitter clinical testing This variant is denoted VHL c.221T>C at the cDNA level, p.Val74Ala (V74A) at the protein level, and results in the change of a Valine to an Alanine (GTC>GCC). This variant has been observed in at least one individual with clear-cell renal cell carcinoma (van Houwelingen 2005, Nordstrom-O'Brien 2010). VHL Val74Ala was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. VHL Val74Ala occurs at a position that is conserved across species and is located within the beta domain (Yuen 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether VHL Val74Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000698497 SCV000827164 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-04-13 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 74 of the VHL protein (p.Val74Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 422125). 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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