Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001380442 | SCV001578523 | pathogenic | Glycogen storage disease, type II | 2020-08-27 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine with proline at codon 405 of the GAA protein (p.Leu405Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Pompe disease (PMID: 14695532, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. 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. |
| Victorian Clinical Genetics Services, |
RCV001380442 | SCV002768747 | likely pathogenic | Glycogen storage disease, type II | 2019-08-28 | criteria provided, single submitter | clinical testing | A heterozygous missense variant was identified, NM_000152.3(GAA): c.1214T>C in exon 8 of 20 of the GAA gene. This substitution is predicted to create a moderate amino acid change from leucine to proline at position 405 of the protein, NP_000143.2(GAA):p.(Leu405Pro). The leucine at this position has low conservation (100 vertebrates, UCSC), and is located within the GH31_MGAM_SI_GAA domain. In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. The variant has been previously reported in a homozygous state in a patient with infantile-onset glycogen storage disease (Hermans M.P et al (2004)). The POMPE database lists the variant as CRIM positive and severe (Kroos M., et al (2008) and Hermans M.P., et al (2004)). Functional studies show that this variant causes enzyme deficiency due to impeded protein maturation, with little or no residual activity (Hermans M.P., et al (2004)). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. |