ClinVar Genomic variation as it relates to human health

p.Ala8Ser (GCT>TCT): c.22 G>T in exon 1 of the OPA1 gene (NM_015560.2). The A8S variant of unknown significance has been published as a mutation in a patient with ADOA who also had a family history of optic atrophy; however, the authors do not state whether or not other family members were tested for A8S (Han et al., 2006). A8S has not been reported as a benign polymorphism to our knowledge, and the A8S variant was not observed in approximately 6200 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 A8S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).

This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Optic atrophy 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 8 of the OPA1 protein (p.Ala8Ser). This missense change has been observed in individual(s) with optic atrophy (PMID: 16617242). 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. 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 not expected to disrupt OPA1 protein function. ClinVar contains an entry for this variant (Variation ID: 193386).