ClinVar Genomic variation as it relates to human health

This variant is present in population databases (rs773592266, gnomAD 0.006%). 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 variant disrupts the p.Arg58 amino acid residue in DARS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24566671, 26327357, 33977142). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 DARS2 protein function. This variant has not been reported in the literature in individuals affected with DARS2-related conditions. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 58 of the DARS2 protein (p.Arg58His).

The c.173G>A (p.R58H) alteration is located in exon 2 (coding exon 2) of the DARS2 gene. This alteration results from a G to A substitution at nucleotide position 173, causing the arginine (R) at amino acid position 58 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.