ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.194C>G (p.Ser65Trp) (rs5030826)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497340 SCV000589600 pathogenic not provided 2018-06-12 criteria provided, single submitter clinical testing The S65W variant has previously been published in association with von Hippel-Lindau syndrome, and was found to have occurred de novo in at least one individual (for examples, see Maher et al., 1996; Hes et al., 2007; Zhang et al., 2015). Functional studies show S65W significantly decreases the VHL protein binding to HIF-1alpha, preventing ubiquitination (Miller et al., 2005). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S65W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and is located within the beta domain (Yuen et al., 2009). Missense variants at the same residue (S65P, S65A, S65L) have been reported in association with VHL-related disorders, supporting the functional importance of this region of the protein (Crossey et al., 1994; Dollfus et al., 2002; Neumann et al., 2002). Based on the currently available information, we consider S65W to be pathogenic.
Invitae RCV001219547 SCV001391491 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-07-22 criteria provided, single submitter clinical testing This sequence change replaces serine with tryptophan at codon 65 of the VHL protein (p.Ser65Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several families affected with Von Hippel-Lindau (VHL) syndrome (PMID: 7728151, 7987306, 8730290, 9829911, 10567493, 17024664, 22799452, 23384228). This variant is also known as Ser136Trp in the literature. ClinVar contains an entry for this variant (Variation ID: 43597). This variant has been reported to affect VHL protein function (PMID: 11331613, 15611064, 16669786, 18544564, 19602254). This variant disrupts the p.Ser65 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10567493, 12114495,15611064, 22799452, 25282218). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036539 SCV000060194 pathogenic Von Hippel-Lindau syndrome 2008-07-30 no assertion criteria provided clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000036539 SCV000264669 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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