Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000672387 | SCV000797486 | likely pathogenic | Glycogen storage disease, type II | 2018-01-28 | criteria provided, single submitter | clinical testing | |
| Broad Center for Mendelian Genomics, |
RCV000672387 | SCV001422989 | pathogenic | Glycogen storage disease, type II | 2020-01-22 | criteria provided, single submitter | curation | The p.Asp645Tyr variant in GAA has been reported in four individuals with glycogen storage disease II, segregated with disease in 2 affected relatives from 1 family (PMID: 18425781, 17616415; DOI: 10.1016/j.jns.2015.08.1211) and has been identified in 0.007% (1/15154) of African chromosomes and 0.003% (1/33952) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368438393). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as likely pathogenic by Counsyl (VariationID: 556386). In vitro studies using cells transfected with the variant provide some evidence that the p.Asp645Tyr variant may impact protein function (PMID: 18425781). However, these types of assays may not accurately represent biological function. Three additional pathogenic variants, resulting in a different amino acid change at the same position (p.Asp645Asn, p.Asp645His, and p.Asp645Glu) have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (VariationID: 188728, 189013, 4029). 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 being <20% of wild type, consistent with disease (PMID: 17616415). Additionally, the presence of this variant in combination with reported pathogenic variant c.-32-13T>G (VariationID: 4027; PMID: 17616415, https://doi.org/10.1016/j.jns.2015.08.1211) and in individuals with glycogen storage disease II silghtly increases the likelihood that the p.Asp645Tyr variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on functional studies demonstrating a potential impact on the protein, previous reports of other pathogenic variants at the same location, and the presence of the variant in combination with a pathogenic variant in an affected individual. ACMG/AMP Criteria applied: PM5_Strong, PS3, PM2, PM3_Supporting, PP3, PP4 (Richards 2015). |
| Invitae | RCV000672387 | SCV002212531 | pathogenic | Glycogen storage disease, type II | 2023-10-16 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 645 of the GAA protein (p.Asp645Tyr). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Pompe disease (PMID: 17616415, 24715333). ClinVar contains an entry for this variant (Variation ID: 556386). 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. This variant disrupts the p.Asp645 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10338092, 21039225, 21232767, 21439876, 21757382, 24269976). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Prevention |
RCV003411583 | SCV004111356 | likely pathogenic | GAA-related condition | 2022-12-21 | criteria provided, single submitter | clinical testing | The GAA c.1933G>T variant is predicted to result in the amino acid substitution p.Asp645Tyr. This variant, along with a second pathogenic GAA variant, has been reported in multiple individuals with glycogen storage disease 2 (Gort et al. 2007. PubMed ID: 17616415; van Gelder et al. 2015. PMID: 24715333; Figueroa-Bonaparte et al. 2016 PMID: 27711114; Ebbink et al. 2018. PMID:29573408; Amiñoso et al. 2022. PubMed ID: 34530085). In the fibroblasts of an individual that was also heterozygous for the c.-32-13T>G variant had residual GAA activity of ~20% (Gort et al. 2007. PubMed ID: 17616415). This variant is reported in 0.0066% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78086719-G-T). This variant is interpreted as likely pathogenic. |
| Baylor Genetics | RCV000672387 | SCV004195467 | pathogenic | Glycogen storage disease, type II | 2023-09-30 | criteria provided, single submitter | clinical testing |