ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.233A>C (p.Asn78Thr) (rs5030804)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000679024 SCV000805329 pathogenic not provided 2014-04-16 criteria provided, single submitter clinical testing
Invitae RCV000805326 SCV000945278 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-08-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with threonine at codon 78 of the VHL protein (p.Asn78Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in families affected with von Hippel-Lindau syndrome (PMID: 7728151) and suspected von Hippel-Lindau syndrome (PMID: 18446368, Invitae). ClinVar contains an entry for this variant (Variation ID: 223168). 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. Variants that disrupt the p.Asn68 amino acid residue in VHL have been observed in affected individuals (PMID: 7728151, 8956040, 12114495, 15109448, 15300849, 19464396, 23842656). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000208838 SCV000264677 likely pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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