ClinVar

Description

The A99V variant in the PSAT1 gene has been reported previously in the homozygous or compound heterozygous state in multiple unrelated individuals with Neu-Laxova syndrome (Acuna-Hidalgo et al., 2014). The A99V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A99V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. As an alternate mechanism, splice predictor models show that c.296_297delCTinsTG (A99V) creates a cryptic donor splice site, which may result in abnormal gene splicing. Based on the available information, we now interpret A99V as a strong candidate for a disease-causing mutation; however, the possibility it may be a rare benign variant cannot be excluded.