Submissions for variant NM_000152.5(GAA):c.692+1G>C

dbSNP: rs773281453

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001249008	SCV005903297	pathogenic	Glycogen storage disease, type II	2025-01-07	reviewed by expert panel	curation	The NM_000152.5:c.692+1G>C variant alters the canonical donor splice site of intron 3 of GAA. It is predicted to cause skipping of biologically-relevant-exon 4 (GAA has 20 exons), resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. A fibroblast cell line derived from a patient who is compound heterozygous for the variant showed reduced GAA enzyme activity via a fluorometric assay using 4-MU. The relative GAA enzyme activity was 3.2% (normal range of GAA activity in fibroblasts is 58.5 +/- 28.1%) (PMID: 19046416). Additionally, RT-PCR analysis performed on cultured fibroblasts from a patient who is compound heterozygous for the variant showed lack of the corresponding mutant transcript, confirming its deleterious effect (PMID: 16917947) (PVS1). At least two patients with findings consistent with Pompe disease have been reported with this variant. Reduced GAA activity was reported for both patients but laboratory values were not provided. One patient, diagnosed with Pompe disease at 5 years of age, showed increased CK levels at 4 years and started ERT at 11 years (PMID: 24395639). The second patient was diagnosed with Pompe disease and presented with clinical features including mild muscular symptoms, mobility problems, weakness and fatigue (PMID: 1691794) (PP4_Moderate). These two patients are compound heterozygous for the variant and another variant in GAA, either c.-32-13T>G (PMID: 16917947) or c.1645G>C (p.G549R) (PMID: 24395639); the phase of the variants is unknown. The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. (PM3_Supporting). In gnomAD v4.1.0, the highest population minor allele frequency is 0.0000008522 (1/1173500 alleles; 0 homozygotes) in the European, (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In gnomAD v2.1.1, the highest population minor allele frequency is 0.000008988 (1/111256 alleles; 0 homozygotes) in the European, (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000008522 (1/1173500 alleles; 0 homozygotes) in the European, (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 972793). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 7, 2025)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249008	SCV001422854	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.692+1G>C variant has been reported in at least two individuals with glycogen storage disease (PMID: 24395639, 19046416, 28182897, 16917947), and has been identified in 0.001% (1/111256) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs773281453). 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 absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease. The phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease based on GAA enzyme activity being <10% of wild type in fibroblasts, consistent with disease (PMID: 28182897, 16917947, 24395639). This variant has been seen in combination with reported pathogenic variant c.-32-13T>G and p.Gly549Arg (VariationID: 4027, PMID: 16917947, 16917947, 28182897, 19046416, 24395639) in individuals with glycogen storage disease. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease in an autosomal recessive manner based on the prediction that the variant causes loss of function, the detection of the variant in combination with other pathogenic variants in affected individuals, and the low frequency of the variant in the general population. ACMG/AMP Criteria applied: PVS1, PM2, PP4 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001249008	SCV002136351	pathogenic	Glycogen storage disease, type II	2022-04-20	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 972793). Disruption of this splice site has been observed in individuals with Pompe disease (PMID: 16917947). This variant is present in population databases (rs773281453, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 3 of the GAA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923).
GeneDx	RCV004719116	SCV005325552	pathogenic	not provided	2023-12-28	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect on splicing resulting in absent transcript (PMID: 16917947); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33426149, 28182897, 25525159, 24395639, 19046416, 16917947, 19862843, 17915575, 20308911, 17213836, 21179066)