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

dbSNP: rs796051877

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000186551	SCV001422885	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	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).
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