ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.36G>C (p.Glu12Asp) (rs973493604)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483032 SCV000567695 uncertain significance not provided 2016-10-11 criteria provided, single submitter clinical testing This variant is denoted VHL c.36G>C at the cDNA level, p.Glu12Asp (E12D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). This variant was observed in an individual with an isolated brain/spinal cord hemangioblastoma (Leonardi 2011). VHL Glu12Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. VHL Glu12Asp occurs at a position that is not conserved and is not located in a known functional domain (Yuen 2009, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether VHL Glu12Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000538470 SCV000626899 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-03-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 12 of the VHL protein (p.Glu12Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with a haemangioblastoma of the central nervous system or the spinal cord (PMID: 21463266). ClinVar contains an entry for this variant (Variation ID: 419711). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on VHL function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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