Submissions for variant NM_000152.5(GAA):c.-32-2A>G

dbSNP: rs1445232530

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	RCV001249079	SCV001423034	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.-32-2A>G variant in GAA has been reported in 3 Colombian siblings with Glycogen Storage Disease II (PMID: 23430493) and has been identified in 0.001% (1/105716) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1445232530). 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 occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease. This variant has been seen in combination with a reported pathogenic variant, p.Gly828_Asn882del (Variation ID: 4031, PMID: 23430493, 7945303, 10737124), and in three individuals with Glycogen Storage Disease II (PMID: 23430493). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001249079	SCV002103370	pathogenic	Glycogen storage disease, type II	2022-02-28	criteria provided, single submitter	clinical testing	Variant summary: GAA c.-32-2A>G 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 3' prime acceptor site. Experimental evidence supports these predictions demonstrating the variant causes skipping of exon 2 (Goina_2019). The variant allele was found at a frequency of 4.3e-06 in 233126 control chromosomes (gnomAD). c.-32-2A>G has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (examples: Kroos_2008 and Nino_2013). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.