ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1437G>A (p.Lys479=) (rs796051877)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Freeman-Sheldon Research Group,deGruyter-McKusick Institute of Health Sciences RCV000186551 SCV000211952 pathogenic Glycogen storage disease, type II 2014-12-21 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000186551 SCV001422885 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The c.1437G>A (p.Lys479=) variant in GAA has been reported in 4 individuals (including 1 from the UK, 1 Guatemalan, and 1 Arabic individuals) with Glycogen Storage Disease II (PMID: 26873529, 18425781, 25243733, 26160551), and has also been reported pathogenic by the Freeman-Sheldon Research Group (deGruyter-McKusick Institute of Health Sciences) in ClinVar based on a case family (Variation ID: 188044). This variant has been identified in 0.003% (1/30606) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs796051877). 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 provide some evidence that the c.1437G>A variant may impact GAA expression and splicing (PMID: 18425781, 25243733). However, these types of assays may not accurately represent biological function. This variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational prediction tools and conservation analyses suggest that this variant may impact splicing, though this information is not predictive enough to determine pathogenicity. The presence of this variant in the homozygous state and in an individual with Glycogen Storage Disease II increases the likelihood that the c.1437G>A variant is pathogenic (PMID: 25243733). The phenotype of an individual homozygous for this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity detected in their fibroblasts (PMID: 25243733). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_Supporting, PP3, PP4, PM2, PS3_Supporting (Richards 2015).

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