Submissions for variant NM_000152.5(GAA):c.1626C>G (p.Pro542=)

gnomAD frequency: 0.00001  dbSNP: rs947585663

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001205756	SCV002540661	uncertain significance	Glycogen storage disease, type II	2022-05-11	reviewed by expert panel	curation	The NM_000152.5:c.1626C>G variant in GAA is a synonymous (silent) variant that is predicted to impact splicing by creating a new donor splice site in exon 11 (PP3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/113310 alleles) in the European (non-Finnish) population (PM2_Supporting). The variant was found homozygous in one patient with late-onset Pompe disease (PM3_supporting), but residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 16917947). Experimental studies demonstrated that the variant impacts splicing by creating a de novo donor site in exon 11 as well as activating a cryptic acceptor site in exon 12, resulting in the deletion of 11 nucleotides from exon 11 and 46 nucleotides from exon 12. A low level of normal transcript was also detected (PMID 21179066)(PS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 430167, 1 star review status) with conflicting interpretations. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP3, PM2_Supporting, PM3_Supporting, PS3_Supporting.
GeneDx	RCV000493261	SCV000582899	likely pathogenic	not provided	2016-06-28	criteria provided, single submitter	clinical testing	The c.1626 C>G variant has previously been reported in association with adult-onset Pompe disease in an individual who was apparently homozygous for c.1626 C>G (Montalvo et al., 2006). Functional analysis of c.1626 C>G found that it results in the creation of a new splice donor site as well as activating a cryptic splice site leading to abnormal gene splicing, although low amounts of a transcript similar in size to normal spliced GAA was also detected by this analysis (Zampieri et al., 2011). Therefore we interpret c.1626 C>G to be a likely pathogenic variant; however, the possibility that it is benign cannot be excluded.
Invitae	RCV001205756	SCV001377029	pathogenic	Glycogen storage disease, type II	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change affects codon 542 of the GAA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GAA protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 19 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has been observed in individual(s) with Pompe disease (PMID: 16917947). ClinVar contains an entry for this variant (Variation ID: 430167). Studies have shown that this variant results in the activation of a cryptic splice site in exon 12 (PMID: 21179066). This variant disrupts a region of the GAA protein in which other variant(s) (p.Ile557Phe) have been determined to be pathogenic (PMID: 23884227). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001205756	SCV001422901	uncertain significance	Glycogen storage disease, type II	2020-01-29	criteria provided, single submitter	curation	The homozygous c.1626C>G (p.Pro542=) variant in GAA has been reported in one Italian individual with Glycogen Storage Disease II (PMID: 16917947) and has been reported likely pathogenic by GeneDx in ClinVar (Variation ID: 430167). This variant has been identified in 0.002% (2/113310) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs947585663). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies with minigene constructs provide some evidence that the c.1626C>G variant may cause abnormal splicing, though there was also evidence of some normally spliced mRNA (PMID: 21179066). The abnormal splicing caused by this variant removes 11 nucleotides from exon 11 and 46 nucleotides from exon 12 due to activation of cryptic splice sites but does not alter the protein reading-frame. It is unclear if this deletion will impact the protein. However, these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PS3_Supporting, PP3 (Richards 2015).
Genome-Nilou Lab	RCV001205756	SCV001810617	uncertain significance	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001205756	SCV004195522	likely pathogenic	Glycogen storage disease, type II	2023-07-30	criteria provided, single submitter	clinical testing