Submissions for variant NM_000152.5(GAA):c.1564C>A (p.Pro522Thr)

dbSNP: rs892129065

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519755	SCV000617643	likely pathogenic	not provided	2017-07-03	criteria provided, single submitter	clinical testing	The P522T variant has been reported in a patient who presented at the age of 10 years with glycogen storage disease type II (GSDII) who also harbored the c.-32-13 T>G pathogenic variant in the GAA gene (McCready et al. 2007). The P522T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P522T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. P522 is located at the end of a beta-strand before and alpha-helical region of the alpha-glucosidase protein and replacement of the Proline at this position may cause misfolding of the protein (Pittis et al., 2008). Furthermore a missense variant at the same residue (P522A) have also been reported in a patient with GSDII, and functional analysis of this other variant found that it is associated with no residual enzyme activity (Pittis et al., 2008). In summary, we interpret P522T as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001834682	SCV003442522	pathogenic	Glycogen storage disease, type II	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 522 of the GAA protein (p.Pro522Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive glycogen storage disease type II (GSDII) (PMID: 17723315). ClinVar contains an entry for this variant (Variation ID: 449460). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. This variant disrupts the p.Pro522 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17643989, 18429042, 26800218, 29422078). 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.
Natera, Inc.	RCV001834682	SCV002092042	likely pathogenic	Glycogen storage disease, type II	2020-09-28	no assertion criteria provided	clinical testing