ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.422A>G (p.Asn141Ser) (rs1064796570)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479780 SCV000573399 uncertain significance not provided 2017-02-16 criteria provided, single submitter clinical testing This variant is denoted VHL c.422A>G at the cDNA level, p.Asn141Ser (N141S) 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 either a pathogenic or benign germline variant. However, it has been reported as a somatic variant in a clear cell renal carcinoma (Khaliq 2014). VHL Asn141Ser 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 Asn141Ser occurs at a position that is conserved in mammals and is located in the region involved in binding to the CCT complex, the beta-domain which interacts with the hydroxylated oxygen-dependent degradation domain of HIF-alpha subunits, and is involved in nuclear export (Yuen 2009, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether VHL Asn141Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000570825 SCV000675823 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-13 criteria provided, single submitter clinical testing The p.N141S variant (also known as c.422A>G), located in coding exon 2 of the VHL gene, results from an A to G substitution at nucleotide position 422. The asparagine at codon 141 is replaced by serine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.005% (greater than 20000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001066733 SCV001231750 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-07-12 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 141 of the VHL protein (p.Asn141Ser). 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). This variant has not been reported in the literature in individuals with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 423677). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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