ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1076-1G>C

gnomAD frequency: 0.00001  dbSNP: rs1555600050
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV002049620 SCV003852735 pathogenic Glycogen storage disease, type II 2023-03-07 reviewed by expert panel curation The NM_000152.5:c.1076-1G>C variant in GAA occurs within the canonical splice acceptor site of intron 6. RT-PCR of fibroblast RNA from a patient who is heterozygous for the variant revealed the inclusion of 79 bp of intron 6 and and 89 bp of intron 7 into the transcript, which is predicted to lead to a frameshift and nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 16917947) (PVS1). Six patients have been reported including one who is homozygous for the variant with symptoms consistent with infantile onset Pompe disease and documentation of deficient GAA activity meeting the specifications of the ClinGen LD VCEP, two compound heterozygous patients with later onset symptoms and documentation of deficient GAA activity, and three patients with symptoms of Pompe disease and re[ported to have reduced GAA activity but for whom individual residual GAA activity was not provided or did not meet criteria (PMID: 16917947, 17616415) (PP4_Moderate). This variant was the second most common variant in a Spanish cohort with Pompe disease, accounting for 6/44 alleles (14%) (PMID: 17616415). One patient is compound heterozygous for the variant and another pathogenic variant in GAA, c.-32-13T>G, phase unknown, 0.5 points (PMID: 16917947), and one patient is homozygous for the variant, 0.5 points (PMID: 17616415). Another four patients are compound heterozygous for the variant and another GAA variant. The allelic data from these patients will be used in the assessment of the second variant and it not included here to avoid circular logic (PMID: 17616415). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1353052). 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 LD VCEP (specifications version 2.0): PVS1, PP4_Moderate, PM3, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV002049620 SCV002110124 pathogenic Glycogen storage disease, type II 2021-10-09 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 the inclusion of intron 6 and intron 7 (PMID: 16917947). Experimental studies have shown that disruption of this splice site affects GAA function (PMID: 17616415). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Disruption of this splice site has been observed in individuals with glycogen storage disease type II (PMID: 16917947, 17616415). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 6 of the GAA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the gain of 56 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.
Fulgent Genetics, Fulgent Genetics RCV002049620 SCV002811626 pathogenic Glycogen storage disease, type II 2021-12-10 criteria provided, single submitter clinical testing

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