ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.525del (p.Glu176fs) (rs386834235)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078181 SCV000227027 pathogenic not provided 2016-08-30 criteria provided, single submitter clinical testing
GeneDx RCV000078181 SCV000321684 pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing The c.525delT pathogenic variant in the GAA gene has been reported previously in association with autosomal recessive Pompe disease when present in the homozygous state or when in trans with another disease-causing variant (Beltran et al., 2014; Kroos et al., 1995). Additionally, studies in leukocytes and muscle fibers predicted the c.525delT variant to be pathogenic based on residual GAA enzyme activity (Remiche et al., 2014). The c.525delT variant causes a frameshift starting with codon Glutamic acid 176, changes this amino acid to a Arginine residue, and creates a premature Stop codon at position 45 of the new reading frame, denoted p.Glu176ArgfsX45. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.525delT variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.525delT as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000004248 SCV000407262 pathogenic Glycogen storage disease, type II 2017-04-28 criteria provided, single submitter clinical testing The GAA c.525delT (p.Glu176ArgfsTer45) variant results in a frameshift, and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Glu176ArgfsTer45 variant has been identified in at least 45 individuals with glycogen storage disease, type II, including seven in a homozygous state, 36 in a compound heterozygous state, and two affected individuals in a heterozygous state in whom a second variant was not identified (Hermans et al. 1994; Kroos et al. 1995; Hirschhorn et al. 1999; Wens et al. 2012; Beltran et al. 2014; Remiche et al. 2014; Bergsma et al. 2015; Mori et al. 2016; van Capelle et al. 2016). The variant was absent from at least 203 controls but is reported at a frequency of 0.00011 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in individual fibroblasts showed that the p.Glu176ArgfsTer45 variant resulted in one percent of enzyme activity compared to controls and completely prohibited formation of lysosomal alpha-glucosidase protein in COS-1 cells (Hermans et al. 1994; Wens et al. 2012; Bergsma et al. 2015). Due to the potential impact of frameshift variants and the collective evidence, the p.Glu176ArgfsTer45variant is classified as pathogenic for glycogen storage disease, type II. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000004248 SCV000626617 pathogenic Glycogen storage disease, type II 2020-01-02 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 2 of the GAA mRNA (c.525delT), causing a frameshift at codon 176. This creates a premature translational stop signal (p.Glu176Argfs*45) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic. This particular variant has been reported in multiple individuals affected with Pompe disease and is known to be a common cause of the disease in the Dutch population (PMID: 8558570, 14695532, 21439876, 22676651, 24158270). While in the compound heterozygous state it has been associated with infantile-, juvenile-, and adult-onset forms, in the homozygous state it has invariably been associated with the infantile-onset form (PMID: 14695532, 18429042, 25243733). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000004248 SCV000919372 pathogenic Glycogen storage disease, type II 2017-09-05 criteria provided, single submitter clinical testing Variant summary: The GAA c.525delT (p.Glu176ArgfsX45) variant results in a premature termination codon, predicted to cause a truncated or absent GAA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 8/113628 control chromosomes at a frequency of 0.0000704, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). The variant has been reported in multiple affected individuals via publications and showed abolished to very little activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Myriad Women's Health, Inc. RCV000004248 SCV001193835 pathogenic Glycogen storage disease, type II 2019-12-09 criteria provided, single submitter clinical testing NM_000152.3(GAA):c.525delT(E176Rfs*45) is classified as pathogenic in the context of Pompe disease. Sources cited for classification include the following: PMID 17056254, 16917947, 24158270, 7881422, 8558570, 24590251 and 16702877. Classification of NM_000152.3(GAA):c.525delT(E176Rfs*45) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078181 SCV001245684 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
OMIM RCV000004248 SCV000024414 pathogenic Glycogen storage disease, type II 1994-12-01 no assertion criteria provided literature only
GeneReviews RCV000004248 SCV000086730 pathologic Glycogen storage disease, type II 2013-05-09 no assertion criteria provided curation Converted during submission to Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000078181 SCV000800858 pathogenic not provided 2016-09-15 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000004248 SCV001422757 pathogenic Glycogen storage disease, type II 2020-01-23 no assertion criteria provided curation The p.Glu176ArgfsTer45 variant in GAA has been reported in at least 77 individuals (including 10 Italian, 6 Dutch, 5 from the UK, 2 Australian, 1 German, and 1 Brazilian individuals) with Glycogen Storage Disease II, segregated with disease in 7 affected relatives from 3 families (PMID: 17723315, 7881422, 23000108, 22980766, 12923862, 16917947, 25243733, 18429042, 14695532, 8990003, 18607768, 19588081, 26497565, 24158270, 27189384, 8558570, 27142047, 24590251, 23430912), and has also been reported pathogenic (by EGL, GeneDx, Illumina, Counsyl, Invitae, Mayo Clinic Genetic Testing Laboratories, OMIM, and GeneReviews) in ClinVar (Variation ID: 4033). This variant has been identified in 0.019% (23/122326) of European (non-Finnish) chromosomes and 0.017% (4/23634) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs386834235). 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 p.Glu176ArgfsTer45 variant may impact GAA expression and activity (PMID: 7881422, 25243733). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 176 and leads to a premature termination codon 45 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. This variant has been seen in homozygous and compound heterozygous patients curated by our study (PMID: 18429042, 14695532, 26497565, 23430912, 17723315, 7881422, 22980766, 16917947, 25243733, 8990003, 18607768, 19588081, 24158270, 27189384, 8558570, 24590251). The phenotype of at least 20 individuals with the variant in the compound heterozygous or homozygous state is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity detected in cultured fibroblasts or muscle cells (PMID: 24158270, 8558570). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PM2, PP4 (Richards 2015).

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