ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.535G>A (p.Asp179Asn) (rs767780451)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478979 SCV000568003 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing This variant is denoted VHL c.535G>A at the cDNA level, p.Asp179Asn (D179N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). This variant was observed in a patient with isolated hemangioblastoma, whose unaffected, 63 year old parent also carried this variant (Woodward 2007). VHL Asp179Asn was not observed in approximately 6,500 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 Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. VHL Asp179Asn occurs at a position where amino acids with properties similar to Aspartic Acid are tolerated across species and is located in the Elongin C binding 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 Asp179Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000705398 SCV000834393 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-06-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 179 of the VHL protein (p.Asp179Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs767780451, ExAC 0.002%). This variant has been observed in an individual affected with cerebellar haemangioblastoma (PMID: 17264095). ClinVar contains an entry for this variant (Variation ID: 419861). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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