ClinVar

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 231 of the ASPA protein (p.Tyr231His). This variant is present in population databases (rs778203652, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ASPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 2129207). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASPA protein function. This variant disrupts the p.Tyr231 amino acid residue in ASPA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10564886, 22850825). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.