Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV001905386 | SCV002133506 | uncertain significance | Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic | 2021-06-28 | criteria provided, single submitter | clinical testing | 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 expected to disrupt GBE1 protein function. This variant has not been reported in the literature in individuals with GBE1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 437 of the GBE1 protein (p.Met437Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. |
Molecular Genetics, |
RCV002225144 | SCV002503617 | uncertain significance | Adult polyglucosan body disease | 2023-03-30 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace methionine with valine at codon 437 of the GBE1 protein (p.Met437Val). The methionine residue is highly conserved (100 vertebrates, UCSC), and is located between the two of the positions that form the catalytic triad (Asp357-Glu412-Asp481) in the catalytic domain (PMID: 26199317). There is a small physicochemical difference between methionine and valine. The variant is absent in a large population cohort (gnomAD v2.1 - PM2), and it has not been reported in the relevant medical literature and databases. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms - PP3). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as a VARIANT of UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2, PP3. |