Submissions for variant NM_000152.5(GAA):c.1438-2A>G

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000631061	SCV001371722	pathogenic	Glycogen storage disease, type II	2020-03-30	reviewed by expert panel	curation	The c.1438-2A>G variant alters the canonical acceptor splice site of intron 9 and has been shown by RT-PCR to causing skipping of exon 10, resulting in an in frame deletion that removes about 4% of the gene product (PMID 24158270). Exon 10 forms part of the GAA catalytic barrel, including two residues, Trp481 and Trp516, which are part of the GAA active site (PMIDs 1856189; 22253258; DOI 10.1101/212837). Therefore, loss of this exon is expected to abolish GAA activity, and PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant has been reported in two individuals with Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4, and who are compound heterozygotes for this variant and a second pathogenic variant, c.-32-13T>G in one case (PMIDs 24158270), and c.955+1G>A in the other (PMID 29422078), meeting PM3. Other variants altering the same canonical splice site, c.1438-1G>T (PMID 18425781) and c.1438-1G>C (PMIDs 22538254, 24495340), have been reported in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 526521) with one submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4.
Invitae	RCV000631061	SCV000752051	pathogenic	Glycogen storage disease, type II	2023-06-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (PMID: 24158270). ClinVar contains an entry for this variant (Variation ID: 526521). Disruption of this splice site has been observed in individual(s) with late onset glycogen storage disease type II (PMID: 24158270). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 of the GAA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
Counsyl	RCV000631061	SCV000788594	likely pathogenic	Glycogen storage disease, type II	2017-04-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000631061	SCV002092032	pathogenic	Glycogen storage disease, type II	2020-08-03	no assertion criteria provided	clinical testing

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