ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1564C>T (p.Pro522Ser)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001248865 SCV001426789 likely pathogenic Glycogen storage disease, type II 2020-07-12 criteria provided, single submitter clinical testing Variant summary: GAA c.1564C>T (p.Pro522Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251280 control chromosomes. c.1564C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease, e.g. Kroos_2008, Kishnani_2019, Reuser_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (Kroos_2012). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001248865 SCV001563199 uncertain significance Glycogen storage disease, type II 2020-10-12 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 522 of the GAA protein (p.Pro522Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GAA-related conditions. Experimental studies have shown that this variant affects GAA protein function (PMID: 22644586). 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, 29422078, 18429042, 26800218). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Nilou-Genome Lab RCV001248865 SCV001810614 likely pathogenic Glycogen storage disease, type II 2021-07-22 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001248865 SCV001422540 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Pro522Ser variant in GAA has been reported in one individual with glycogen storage disease II (PMID: 18425781) and has been identified in 0.002% (2/113602) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs892129065). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies using COS cells transfected with the variant provide some evidence that the p.Pro522Ser variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Pro522Thr and p.Pro522Ala, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (VariationID: 44946, 371277). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PM5, PP3 (Richards 2015).

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