Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000483104 | SCV000573695 | uncertain significance | not provided | 2017-11-28 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the ADSL gene. The R374Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A different missense substitution at the same position (R374W) has been reported in an individual with seizures, intellectual disability, facial dysmorphism, and biochemical testing consistent with ADSL deficiency; this individual also had a second ADSL variant on the opposite allele (Holder-Espinasse et al., 2002). The R374Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R374Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Invitae | RCV000634533 | SCV000755851 | uncertain significance | Adenylosuccinate lyase deficiency | 2022-08-20 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 374 of the ADSL protein (p.Arg374Gln). This variant is present in population databases (rs568567422, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ADSL-related conditions. ClinVar contains an entry for this variant (Variation ID: 423931). 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 ADSL protein function. This variant disrupts the p.Arg374 amino acid residue in ADSL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12070256; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |