ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.449A>G (p.Asn150Ser) (rs760184234)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410629 SCV000489424 uncertain significance Von Hippel-Lindau syndrome 2016-10-03 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000410629 SCV000897827 uncertain significance Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000483327 SCV000568594 uncertain significance not provided 2017-01-18 criteria provided, single submitter clinical testing This variant is denoted VHL c.449A>G at the cDNA level, p.Asn150Ser (N150S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant, also published as VHL c.662A>G using alternate numbering, was observed as a paternally inherited allele in a child with congenital polycythemia, who also harbored a de novo VHL truncating variant (phase unknown) previously reported in Von Hippel-Lindau patients (Sidhu 2015). VHL Asn150Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. VHL Asn150Ser occurs at a position that is conserved across species and is located in the nuclear export domain/beta-domain and region involved in binding to CCT complex (UniProt, Yuen 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether VHL Asn150Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000534480 SCV000626906 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 150 of the VHL protein (p.Asn150Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs760184234, ExAC 0.001%). This variant has been reported in an individual affected with polycythemia, who also carried a de novo truncating variant (PMID: 25586603). This variant is also known as c.662A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 371992). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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