ClinVar Miner

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

dbSNP: rs770780848
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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 RCV001375542 SCV001572408 pathogenic Glycogen storage disease, type II 2021-04-07 criteria provided, single submitter clinical testing Variant summary: GAA c.1551+1G>A 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 a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in exon 10 skipping (Bergsma_2015). The variant was absent in 251156 control chromosomes. c.1551+1G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Mechler_2012, Bergsma_2015, Figueroa-Bonaparte_2016, Papadopoulos_2017, Poelman_2018, Semplicini_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in fibroblasts and leukocytes from a patient homozygous for this variant (example, Poelman_2018). 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 pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001375542 SCV002217225 pathogenic Glycogen storage disease, type II 2022-05-12 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1065143). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with Pompe disease (PMID: 22133539, 25243733, 28648663). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 10 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).
Natera, Inc. RCV001375542 SCV002092041 pathogenic Glycogen storage disease, type II 2020-04-20 no assertion criteria provided clinical testing

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