ClinVar Miner

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

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Total submissions: 8
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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 2020-10-13 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 in individual(s) with glycogen storage disease (PMID: 25243733, 16838077, 28196920, 23430949). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000593914 SCV001370134 pathogenic Glycogen storage disease, type II 2019-01-09 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
Counsyl RCV000593914 SCV000792707 uncertain significance Glycogen storage disease, type II 2018-12-28 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000593914 SCV001422910 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The c.1552-3C>G variant in GAA has been reported in 3 individuals with Glycogen Storage Disease II (PMID: 16838077, 25243733, 28196920) and has also been reported likely pathogenic by Counsyl, Invitae, and EGL Genetic Diagnostics and pathogenic by GeneDx and Integrated Genetics in ClinVar (Variation ID: 419722). This variant has been identified in 0.027% (35/129024) of European (non-Finnish) chromosomes and 0.008% (3/35432) of Latino chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs375470378). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the c.1552-3C>G variant may cause an impact on splicing in individuals homozygous for this variant with less than 9% of mRNA spliced correctly (PMID: 25243733, 16838077). However, these types of assays may not accurately represent biological function. This variant is located in the 3' splice region. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein, though some splice predictors do suggest an impact on a splice site. The presence of this variant in the homozygous state and in combination with a reported pathogenic variant, and in individuals with Glycogen Storage Disease II increases the likelihood that the c.1552-3C>G variant is pathogenic (PMID: 28196920, 16838077). The phenotype of individuals homozygous and heterozygous with this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in their leukocytes and the absence of known pseudodeficiency alleles in one individual (PMID: 28196920, 16838077). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP4_Moderate, PM3, PM2, PS3_Supporting (Richards 2015).

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