ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1551+1G>C

dbSNP: rs770780848
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV000670717 SCV005619828 pathogenic Glycogen storage disease, type II 2024-10-04 reviewed by expert panel curation The NM_000152.5:c.1551+1G>C variant alters the canonical donor splice site of intron 10 of GAA. Sequence analysis of cDNA from an individual who is compound heterozygous for this variant revealed that the variant results in skipping of exon 10 (GAA has 20 exons). Skipping of exon 10 results in an in-frame deletion of amino acids 480-517. This region forms part of the GAA catalytic barrel (amino acids 347-727) including two residues, Trp481 and Trp516, which are important in active site architecture and substrate binding (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837; Roig-Zamboni et al, 2017, PMID: 29061980). Therefore, loss of this exon is expected to abolish GAA activity (PVS1). At least 7 patients with findings consistent with Pompe disease have been reported with this variant. GAA activity was reported for 2 patients and was deficient (<10% residual activity) (PMID: 7881425, 25673129) (PP4_Moderate). At least 5 patients are compound heterozygous for the variant and c.-32-13T>G (known pathogenic variant) (ClinVar Variation ID: 4027) (phase unknown, max 2 x 0.5 points) (PMID: 7881425, 16917947, 25673129). Two patients are compound heterozygous for the variant and another variant in GAA, either c.1437+2T>C (PMID: 11343339) or c.1755-1G>A (PMID: 17056254); both confirmed in trans. The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. 1 point (PM3). This variant is absent in gnomAD v2.1.1. In gnomAD v4.1.0., the highest population minor allele frequency is 0.000001695 (2/1179958 alleles; 0 homozygotes) which is lower that the ClinGen LD VCEP's threshold for PM2_Supporting (<0.001), in the European non-Finnish population, meeting this criterion (PM2_Supporting). Other variants at the same canonical donor splice site have been reported in patients with Pompe disease, including c.1551+1G>A, c.1551+1G>T, and c.1551+2T>G (www.pompevariantdatabase.nl). These variants have not yet been classified by the ClinGen LD VCEP. There is a ClinVar entry for this variant (Variation ID: 554983). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 4, 2024)
Counsyl RCV000670717 SCV000795609 pathogenic Glycogen storage disease, type II 2017-11-10 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001784264 SCV002023873 pathogenic not provided 2019-12-21 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000670717 SCV002781875 pathogenic Glycogen storage disease, type II 2024-04-26 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000670717 SCV004296874 pathogenic Glycogen storage disease, type II 2024-10-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 10 of the GAA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Pompe disease (PMID: 7881425, 22252923, 33202836). This variant is also known as IVS10 +1GT-CT. ClinVar contains an entry for this variant (Variation ID: 554983). 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: 7881425). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000670717 SCV005058761 pathogenic Glycogen storage disease, type II 2023-12-10 criteria provided, single submitter clinical testing

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