ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.853C>T (p.Pro285Ser) (rs886042086)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723486 SCV000331150 pathogenic not provided 2018-06-13 criteria provided, single submitter clinical testing
Counsyl RCV000383868 SCV000791139 uncertain significance Glycogen storage disease, type II 2017-05-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000383868 SCV000917401 pathogenic Glycogen storage disease, type II 2018-12-13 criteria provided, single submitter clinical testing Variant summary: GAA c.853C>T (p.Pro285Ser) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain of 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 3.7e-05 in 27092 control chromosomes. c.853C>T has been reported in the literature in individuals affected with Late Onset Pompe Disease (Bali_2011, Carlier_2011, Kroos_2008, Nallamilli_2018, Orlikowski_2011), and in one reported case the GAA activity in the patients fibroblasts was <1% (Bali_2011). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000383868 SCV001380489 likely pathogenic Glycogen storage disease, type II 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 285 of the GAA protein (p.Pro285Ser). 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 been observed in several individuals affected with Pompe disease (PMID: 18425781, 21484825, 21550241). ClinVar contains an entry for this variant (Variation ID: 281052). This variant has been reported to affect GAA protein function (PMID: 22644586). This variant disrupts the p.Pro285 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 14695532), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000383868 SCV001422621 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Pro285Ser variant in GAA has been reported in 3 individuals with Glycogen Storage Disease II (PMID: 21550241, 21484825, 30564623), and has also been reported as a pathogenic variant by EGL Genetic Diagnostics and Integrated Genetics and a VUS by Counsyl in ClinVar (Variation ID: 281052). This variant has been identified in 0.013% (3/22640) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs886042086). 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 with COS cells transfected with this variant provide some evidence that the p.Pro285Ser variant may impact GAA activity and slightly reduce GAA levels (PMID: 22644586). However, these types of assays may not accurately represent biological function. 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 presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Pro285Ser variant is pathogenic (PMID: 21550241, 21484825). One additional pathogenic variant at the the same position, p.Pro285Arg, was reported in association with disease, supporting that a change at this position may not be tolerated (Variation ID: 225114). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues, consistent with disease (PMID: 21550241, 21484825). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on evidence from in vitro functional studies, low frequency in the general population, and another pathogenic variant reported at the same position. ACMG/AMP Criteria applied: PS3, PM5, PM2, PM3_Supporting, PP3, PP4 (Richards 2015).

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