ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.233A>T (p.Asn78Ile) (rs5030804)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000803184 SCV000943046 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with isoleucine at codon 78 of the VHL protein (p.Asn78Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Von Hippel-Lindau disease (PMID: 9681856, 12114495, 21673464, Invitae). ClinVar contains an entry for this variant (Variation ID: 223169). 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. This variant disrupts the p.Asn78 amino acid residue in VHL. Other variants that disrupt this residue have been observed in affected individuals (PMID: 7728151, 8956040, 15109448, 23842656), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000208821 SCV000264679 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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