rs386834235
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP4PM3PVS1PM2
This summary comes from the ClinGen Evidence Repository: 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 (http://www.pompevariantdatabase.nl/). 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA220406/MONDO:0009290/010
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00017 ( 0 hom. )
Consequence
GAA
NM_000152.5 frameshift
NM_000152.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -11.2
Genes affected
GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
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Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| GAA | NM_000152.5 | c.525del | p.Glu176ArgfsTer45 | frameshift_variant | 2/20 | ENST00000302262.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GAA | ENST00000302262.8 | c.525del | p.Glu176ArgfsTer45 | frameshift_variant | 2/20 | 1 | NM_000152.5 | P1 |
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GnomAD3 genomes ? AF: 0.000177 AC: 27AN: 152238Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000959 AC: 23AN: 239740Hom.: 0 AF XY: 0.0000987 AC XY: 13AN XY: 131658
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:21Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:14Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 15, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 17, 2021 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1994 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Mar 31, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glycogen storage disease II (MIM#232300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (27 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in infantile and adolescent patients with glycogen storage disease II (PMID: 7881422, 12923862). This variant has also been reported as pathogenic by more than ten laboratories in ClinVar. (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 05, 2017 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Glu176Argfs*45) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is present in population databases (rs386834235, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 8558570, 14695532, 18429042, 21439876, 22676651, 24158270, 25243733). It is commonly reported in individuals of Dutch ancestry (PMID: 8558570, 14695532, 18429042, 21439876, 22676651, 24158270, 25243733). ClinVar contains an entry for this variant (Variation ID: 4033). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Feb 09, 2017 | - - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Nov 02, 2020 | 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 (http://www.pompevariantdatabase.nl/). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 18, 2020 | 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. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 23, 2020 | 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 09, 2019 | 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 - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 30, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | GAA: PM3:Very Strong, PVS1, PM2, PS3:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 26, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 12, 2021 | This sequence change is a single base pair deletion in exon 2, c.525del, that results in an amino acid frameshift and the creation of a premature stop codon 44 amino acids downstream of the change, p.Glu176Argfs*45. This sequence change is predicted to result in an abnormal, truncated GAA protein that is likely to affect its normal function. The p.Glu176Argfs*45 change has been reported in several individuals with Glycogen storage disease II and is a known pathogenic variant common in the Dutch population (PMIDs: 8558570, 14695532, 21439876, 22676651, 24158270). This sequence change has been described in the gnomAD database with a relatively low frequency of 0.019% in the European sub-population. Based on these evidence, the c.525del variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 01, 2023 | PP4, PM3_very_strong, PS3, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Dec 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 29, 2019 | 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) - |
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