ClinVar Miner

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

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen RCV000004248 SCV001443331 pathogenic Glycogen storage disease, type II 2020-11-02 reviewed by expert panel curation This variant, c.525delT (p.Glu176ArgfsTer45), is one of the most common variants reported in individuals with Pompe disease; over 70 patients are listed in the Erasmus database ( It is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by the finding of c.525delT in individuals with no GAA cross-reactive immunological material in cultured skin fibroblasts i.e. CRIM-negative (PMID 22252923, 31342611), no detectable increase in GAA activity or GAA protein when cDNA with the variant was expressed in COS cells (PMID 7881422), and low expression of all GAA exons based on qRT-PCR data from a homozygous patient (PMID 25243733). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000188 in the European non-Finnish population, meeting PM2. Thirty patients meeting the ClinGen LSD VCEP's specifications for PP4 are listed here (PMIDs 8558570, 24590251, 25243733, 26497565, 27142047, 29422078) and include patients who are homozygous for the variant, or compound heterozygous for the variant and either c.-32-13T>G, c.2481+110_2646+39del (exon 18 deletion), c.1802C>A (p.Ser601Ter), c.2608C>T (p.Arg870Ter), c.1548G>A (p.Trp516Ter), c.2237G>A (p.Trp746Ter), and c.670C>T (p.Arg224Trp). The maximum strength for PM3 (PM3_VeryStrong) was applied. There is a ClinVar entry for this variant (Variation ID: 4033, 2 star review status) with 8 laboratory submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Very Strong, PP4.
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 2019-08-29 criteria provided, single submitter clinical testing Expression studies in COS cells show that this variant is associated with a loss of function (Hermans et al., 1994); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18607768, 20301438, 16917947, 22676651, 21228398, 22975760, 23000108, 27142047, 14695532, 29946513, 29149851, 30564623, 27189384, 7945303, 9950376, 24715333, 7881422, 8558570, 24590251, 27460347, 27344650, 29422078, 28951071, 18429042, 24158270, 31676142, 31086307, 31589614, 33202836, 8990003, 32528171, 29556838)
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 2020-10-31 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000004248 SCV001448872 pathogenic Glycogen storage disease, type II 2017-02-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000004248 SCV001473942 pathogenic Glycogen storage disease, type II 2020-02-18 criteria provided, single submitter clinical testing The GAA c.525delT; p.Glu176fs variant (rs386834235) is reported in the literature in the homozygous or compound heterozygous in multiple individuals affected with glycogen storage disease type II, also called Pompe disease (Hermans 1994, Kroos 1995, Remiche 2014, Wens 2012). This variant is found in the general population with an overall allele frequency of 0.01% (27/271120 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Functional studies suggest that cells expressing this variant exhibit no measurable alpha-glucosidase catalytic activity (Hermans 1994). Based on available information, this variant is considered to be pathogenic. References: Hermans MM et al. The effect of a single base pair deletion (delta T525) and a C1634T missense mutation (pro545leu) on the expression of lysosomal alpha-glucosidase in patients with glycogen storage disease type II. Hum Mol Genet. 1994 Dec;3(12):2213-8. Kroos MA et al. Glycogen storage disease type II: frequency of three common mutant alleles and their associated clinical phenotypes studied in 121 patients. J Med Genet. 1995 Oct;32(10):836-7. Remiche G et al. Extended phenotype description and new molecular findings in late onset glycogen storage disease type II: a northern Italy population study and review of the literature. J Neurol. 2014 Jan;261(1):83-97. Wens SC et al. Remarkably low fibroblast acid a-glucosidase activity in three adults with Pompe disease. Mol Genet Metab. 2012 Nov;107(3):485-9.
OMIM RCV000004248 SCV000024414 pathogenic Glycogen storage disease, type II 1994-12-01 no assertion criteria provided literature only
GeneReviews RCV000004248 SCV000086730 pathogenic Glycogen storage disease, type II 2017-05-11 no assertion criteria provided literature only
Mayo Clinic 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,; 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).
Natera, Inc. RCV000004248 SCV001453587 pathogenic Glycogen storage disease, type II 2020-09-16 no assertion criteria provided clinical testing

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