Submissions for variant NM_000152.5(GAA):c.1438-1G>T

dbSNP: rs147804176

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000818785	SCV000959417	pathogenic	Glycogen storage disease, type II	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 9 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). This variant is present in population databases (rs147804176, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with Pompe disease (PMID: 18425781, 22538254, 29122469). ClinVar contains an entry for this variant (Variation ID: 661381). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000818785	SCV001422699	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.1438-1G>T variant in GAA has been reported in two individuals with glycogen storage disease (PMID: 18425781) and has been identified in 0.001% (1/113236) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs147804176). 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. There is an in-frame cryptic splice site 15 bases from the intron-exon boundary, providing evidence that this variant may add 5 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. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_strong, PM2 (Richards 2015).
Revvity Omics, Revvity	RCV001785729	SCV002021185	pathogenic	not provided	2019-08-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000818785	SCV002048896	likely pathogenic	Glycogen storage disease, type II	2021-03-02	criteria provided, single submitter	clinical testing	The GAA c.1438-1G>T variant (rs147804176) is reported in the literature in two individuals affected with Pompe disease (Kroos 2008). This variant is found on a single chromosome in the Genome Aggregation Database (1/250786 alleles), indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 9, which is likely to disrupt gene function. Based on available information, this variant is considered to be likely pathogenic. References: Kroos et al. Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. Hum Mutat. 2008 Jun;29(6):E13-26.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000818785	SCV002555660	pathogenic	Glycogen storage disease, type II	2022-06-06	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1438-1G>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 3' acceptor site. Four predict the variant weakens a 5' donor site. The variant allele was found at a frequency of 4e-06 in 250786 control chromosomes. c.1438-1G>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; examples: Kroos_2008, Banugaria_2011, Desai_2019, Khan_2020). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001785729	SCV003921709	likely pathogenic	not provided	2023-04-28	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26582918, 37087815, 18425781)
Baylor Genetics	RCV000818785	SCV004197780	pathogenic	Glycogen storage disease, type II	2023-07-28	criteria provided, single submitter	clinical testing