ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2482-2A>G

gnomAD frequency: 0.00001  dbSNP: rs756671283
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001582397 SCV001821446 likely pathogenic Glycogen storage disease, type II 2021-08-31 criteria provided, single submitter clinical testing Variant summary: GAA c.2482-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 249940 control chromosomes. c.2482-2A>G has been reported in the literature as a carrier genotype in at-least one individual undergoing newborn screening for Glycogen Storage Disease, Type 2 (Pompe Disease) and has been subsequently cited in the Pompe mutation database (example, Wittmann_2012, de Faria_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001582397 SCV002111600 likely pathogenic Glycogen storage disease, type II 2023-10-25 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 17 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 present in population databases (rs756671283, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with a positive newborn screening result for GAA-related disease (PMID: 23430949). ClinVar contains an entry for this variant (Variation ID: 1217288). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV001582397 SCV004197903 pathogenic Glycogen storage disease, type II 2022-08-03 criteria provided, single submitter clinical testing

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