ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1552-3C>G (rs375470378)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479616 SCV000567714 pathogenic not provided 2015-09-01 criteria provided, single submitter clinical testing The c.1552-3 C>G variant has been previously reported as a homozygous variant in a patient with a mild form of GSDII (Kroos et al., 2006). Functional studies demonstrate that the c.1552-3 C>G variantcauses aberrant gene splicing and results in reduced enzyme activity (Kroos et al., 2006; Bergsma et al., 2015). It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project.Therefore, we interpret c.1552-3 C>G as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000479616 SCV000701459 likely pathogenic not provided 2017-03-16 criteria provided, single submitter clinical testing
Invitae RCV000593914 SCV000819326 likely pathogenic Glycogen storage disease, type II 2019-12-31 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs375470378, ExAC 0.02%). This variant has been observed as homozygous in individuals with low alpha-glucosidase enzyme activity, a finding that is highly specific for glycogen storage disease (PMID: 25243733, 16838077, 28196920, 23430949, Invitae). ClinVar contains an entry for this variant (Variation ID: 419722). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change results in an aberrantly spliced GAA primary transcript (PMID: 16838077, 25243733). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000593914 SCV000917383 pathogenic Glycogen storage disease, type II 2017-11-06 criteria provided, single submitter clinical testing Variant summary: The GAA c.1552-3C>G variant involves the alteration of a non-conserved intronic nucleotide and 5/5 splice prediction tools predict an impact on normal splicing. Multiple functional studies support these predictions with findings indicating that the variant does affect splicing (Kroos_2006, Bergsma_2015). This variant was found in 38/277142 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000276 (35/126638), which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). Multiple publications have cited the variant in homozygous affected individuals. In addition, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000593914 SCV001160509 likely pathogenic Glycogen storage disease, type II 2019-05-11 criteria provided, single submitter clinical testing The GAA c.1552-3C>G variant (rs375470378) is reported in the literature in at least one homozygous individual affected with glycogen storage disease II, also called Pompe disease (Bergsma 2015, Kroos 2006). This variant is found in the non-Finnish European population with an overall allele frequency of 0.03% (35/129024 alleles) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by weakening the nearby canonical acceptor splice site. Consistent with these predictions, analyses of patient cDNAs show production of aberrantly spliced mRNAs and reduced mRNA levels compared to those in healthy individuals (Bergsma 2015, Kroos 2006). In addition, fibroblasts from a homozygous individual with this variant exhibited decreased GAA protein levels and substantially reduced GAA enzymatic activity (Bergsma 2015, Kroos 2006). Based on available information, this variant is considered to be likely pathogenic. References: Bergsma AJ et al. Identification and characterization of aberrant GAA pre-mRNA splicing in pompe disease using a generic approach. Hum Mutat. 2015 Jan;36(1):57-68. Kroos M et al. Seven cases of Pompe disease from Greece. J Inherit Metab Dis. 2006 Aug;29(4):556-63.
Counsyl RCV000593914 SCV000792707 uncertain significance Glycogen storage disease, type II 2018-12-28 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.