ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.233A>G (p.Asn78Ser) (rs5030804)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000254892 SCV000111077 pathogenic not provided 2017-05-03 criteria provided, single submitter clinical testing
GeneDx RCV000254892 SCV000322000 pathogenic not provided 2018-09-06 criteria provided, single submitter clinical testing The N78S missense variant in the VHL gene has been reported previously in association with von Hippel-Lindau syndrome (Chen et al., 1995; Zhang et al., 2008; Qi et al., 2013). It was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. N78S is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense changes at the same (N78I/T/H/Y/D) and in nearby residues (V74G, I75S, F76I/S/L, R79C/P, S80R/G/N/I, P81A/S, R82G/L/P) have been reported in the Human Gene Mutation Database in association with von Hippel-Lindau syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, functional studies of the N78S variant have shown that it is unstable and results in upregulation of HIF-2α and Glut-1, the down regulation of P27, and the disruption of pVHL and hVDU1 interactions in vitro (Bangiyeva et al., 2009; Li et al., 2002). Therefore, the N78S variant is pathogenic.
Ambry Genetics RCV000492165 SCV000580971 pathogenic Hereditary cancer-predisposing syndrome 2018-02-24 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other strong data supporting pathogenic classification
Invitae RCV001034687 SCV000626871 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 78 of the VHL protein (p.Asn78Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several unrelated individuals affected with von Hippel Lindau disease and to co-segregate with disease in at least two families (PMID: 7728151, 8956040, 12114495, 15109448, 15300849, 19464396, 23842656). This variant is also known as N149S in the literature. ClinVar contains an entry for this variant (Variation ID: 93326). Experimental studies have shown that this missense change is not able to functionally rescue VHL-null mammalian cells in culture (PMID: 19602254, 21454469). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000079207 SCV000785647 pathogenic Von Hippel-Lindau syndrome 2017-10-19 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000254892 SCV000805330 pathogenic not provided 2016-11-06 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000079207 SCV000264678 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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