ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.578A>G (p.Asn193Ser) (rs879254225)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236061 SCV000293889 uncertain significance not provided 2016-02-01 criteria provided, single submitter clinical testing This variant is denoted VHL c.578A>G at the cDNA level, p.Asn193Ser (N193S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. VHL Asn193Ser 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 Asn193Ser occurs at a position that is not conserved and is located within the beta-domain (Yuen 2009). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether VHL Asn193Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000537589 SCV000626911 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2017-04-18 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 193 of the VHL protein (p.Asn193Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 246368). 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 tolerated, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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