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

gnomAD frequency: 0.00001  dbSNP: rs770780848

Total submissions: 6

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
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000671915	SCV001422696	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	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).
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.
Fulgent Genetics, Fulgent Genetics	RCV000671915	SCV002810428	pathogenic	Glycogen storage disease, type II	2021-07-23	criteria provided, single submitter	clinical testing
Invitae	RCV000671915	SCV003442563	pathogenic	Glycogen storage disease, type II	2022-04-01	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 10 of the GAA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs770780848, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with Pompe disease (PMID: 25243733, 31086307). ClinVar contains an entry for this variant (Variation ID: 555986). Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (PMID: 25243733). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000671915	SCV003934920	pathogenic	Glycogen storage disease, type II	2023-06-22	criteria provided, single submitter	clinical testing	The homozygous splice site variant c.1551+1G>T has been identified in the proband with phenotypes: respiratory distress, muscle weakness, proximal and distal muscles weakness in lower and upper extremities. This variant has been identified in a proband in a compound heterozygous state with c.1861T>C (p.Trp621Arg) presented with symptoms at 7 months with cardiomegaly, respiratory distress, muscle weakness.