ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.955+1G>A

dbSNP: rs1403691329
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV001200873 SCV001371768 pathogenic Glycogen storage disease, type II 2020-02-14 reviewed by expert panel curation This variant, c.955+1G>A, alters the donor splice site of intron 5 in the GAA gene. Assuming that skipping of exon 5 occurs, this would cause a frameshift, resulting in a premature termination codon and lack of GAA gene product, meeting PVS1. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant was found in compound heterozygosity with a pathogenic variant in GAA, c.1438-2A>G, in a patient who also meets the ClinGen LSD VCEP's PP4 specifications (PMID 29422078). The phase is unknown. This data meets PM3_Supporting. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.
Labcorp Genetics (formerly Invitae), Labcorp RCV001200873 SCV004539060 pathogenic Glycogen storage disease, type II 2024-01-02 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the GAA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). 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: 29422078). ClinVar contains an entry for this variant (Variation ID: 932905). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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