Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Centre for Human Genetics | RCV001293794 | SCV001482498 | benign | Glycogen storage disease type III | 2020-01-09 | criteria provided, single submitter | clinical testing | tolerated |
Invitae | RCV001293794 | SCV004267012 | likely pathogenic | Glycogen storage disease type III | 2023-10-24 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 627 of the AGL protein (p.Asp627Gly). This variant is present in population databases (rs764236940, gnomAD 0.006%). This missense change has been observed in individuals with glycogen storage disease type III (PMID: 32222031). ClinVar contains an entry for this variant (Variation ID: 998107). 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 AGL protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Asp627 amino acid residue in AGL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20490926; 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 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. |