Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV001249044 | SCV001422986 | uncertain significance | Glycogen storage disease, type II | 2020-01-15 | criteria provided, single submitter | curation | The p.Thr653Asn variant in GAA has been reported in three individuals with glycogen storage disease II (PMID: 29995633, 21232767, 24513544) and has been identified in 0.025% (5/19624) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs763456921). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts and lymphocytes being <1% of wild type, consistent with disease (PMID: 21232767, 24513544). This variant has been reported in combination with reported pathogenic and likely pathogenic variants and in individuals with glycogen storage disease II (VariationID: 555986; PMID: 21232767, 24513544, 29995633). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PP4 (Richards 2015). |
| Invitae | RCV001249044 | SCV001573915 | pathogenic | Glycogen storage disease, type II | 2023-09-05 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 653 of the GAA protein (p.Thr653Asn). This variant is present in population databases (rs763456921, gnomAD 0.02%). This missense change has been observed in individual(s) with Pompe disease (PMID: 21232767, 24513544). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 972798). 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 GAA protein function. For these reasons, this variant has been classified as Pathogenic. |
| Baylor Genetics | RCV001249044 | SCV004195473 | likely pathogenic | Glycogen storage disease, type II | 2023-09-24 | criteria provided, single submitter | clinical testing |