ClinVar

Description

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.