ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1551+1G>T (rs770780848)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671915 SCV000796949 pathogenic Glycogen storage disease, type II 2018-01-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000671915 SCV001572465 pathogenic Glycogen storage disease, type II 2021-04-08 criteria provided, single submitter clinical testing Variant summary: GAA c.1551+1G>T 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 5 splicing donor site. Bergsma et al, 2014 report that the variant causes in-frame exon 10 skipping and a leaky wild-type splicing (Bergsma_2014). The variant allele was found at a frequency of 8e-06 in 251156 control chromosomes (gnomAD). c.1551+1G>T has been reported in the literature in multiple individuals (both homozygous and compound heterozygous patients) affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Bergsma_2014, Gupta_2020, Kishnani_2019, Semplicini_2018, Thomas_2021). Several of these patients had juvenile and infantile onset of the disease. These data indicate that the variant is very likely to be associated with disease. Patient homozygous for the variant show reduced alpha-glucosidase activity (Thomas_2021). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000671915 SCV001422696 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The c.1551+1G>T variant in GAA has been reported in five individuals with glycogen storage disease II, segregated with disease in two affected relatives from one family (PMID: 25703594) and has been identified in 0.003% (1/34580) of Latino chromosomes and 0.001% (1/113512) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770780848). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as pathogenic by Counsyl (VariationID: 555986). This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause in-frame exon skipping and a leaky splice site leading to an abnormal or absent protein. There is an in-frame cryptic splice site 6 bases from the intron-exon boundary, providing evidence that this variant may add 2 amino acids instead of causing loss of function. However, this information is not predictive enough to determine pathogenicity. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease II. The phenotype of individuals that are compound heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <10% of wild type, consistent with disease (PMID: 25703594, 25243733). Additionally, the presence of this variation in combination with reported pathogenic variant c.-32-13T>G (VariationID: 4027, PMID: 30155607, 25703594) and likely pathogenic variant p.Asp419Val (PMID: 25243733) and in individuals with glycogen storage disease II increases the likelihood that the c.1551+1G>T variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_moderate, PM3, PM2, PP4 (Richards 2015).

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