ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1437+1G>A (rs1555600575)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671773 SCV000796792 pathogenic Glycogen storage disease, type II 2017-12-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000671773 SCV001572521 pathogenic Glycogen storage disease, type II 2021-04-10 criteria provided, single submitter clinical testing Variant summary: GAA c.1437+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 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 248246 control chromosomes. c.1437+1G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Reuser_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified 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 RCV000671773 SCV001422700 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The c.1437+1G>A variang in GAA has been reported in 4 individuals with glycogen storage disease II (PMID: 22555271, 28266734, 22676651, 22252923) and has been reported in ClinVar as pathogenic by Counsyl (VariationID: 555864). This variant has been identified in 0.003% (1/34538) Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1555600575). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies using an expression vector system demonstrating abnormal splicing provide some evidence that the c.1437+1G>A variant may impact protein function (PMID: 11343339). This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause skipping of exon 9 leading to an absent protein (PMID: 22676651, 22252923, 11343339). Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease II. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_strong, PM2 (Richards 2015).

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