ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.525del (p.Glu176fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000152.5(GAA):c.525del (p.Glu176fs)
Variation ID: 4033 Accession: VCV000004033.69
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80105111 (GRCh38) [ NCBI UCSC ] 17: 78078910 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 1, 2013 Apr 15, 2024 Nov 2, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5(GAA):c.525del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
frameshift NM_000152.5:c.525del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Glu176fs frameshift NM_000152.5:c.525delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001079803.2:c.525del NM_001079803.3:c.525del NP_001073271.1:p.Glu176fs frameshift NM_001079804.3:c.525del NP_001073272.1:p.Glu176fs frameshift NC_000017.11:g.80105111del NC_000017.10:g.78078910del NG_009822.1:g.8556del LRG_673:g.8556del LRG_673t1:c.525del - Protein change
- E176fs
- Other names
- p.Glu176Argfs*45
- Canonical SPDI
- NC_000017.11:80105110:T:
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016
The Genome Aggregation Database (gnomAD) 0.00019
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GAA | - | - |
GRCh38 GRCh38 GRCh37 |
2765 | 2815 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (15) |
reviewed by expert panel
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Nov 2, 2020 | RCV000004248.48 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000078181.37 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 02, 2020)
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reviewed by expert panel
Method: curation
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Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel
Accession: SCV001443331.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000407262.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Sep 05, 2017)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919372.1
First in ClinVar: May 31, 2019 Last updated: May 31, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Aug 30, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000227027.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 10
Sex: mixed
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Pathogenic
(Feb 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473942.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Aug 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002069652.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 23, 2020)
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criteria provided, single submitter
Method: curation
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Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422757.2
First in ClinVar: Jul 19, 2020 Last updated: Jan 29, 2022 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Dec 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502813.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 3
Secondary finding: no
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Pathogenic
(Nov 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580373.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS4, PM3, PM2_SUP, PP1
|
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767502.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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 (less)
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Pathogenic
(Sep 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809707.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004195417.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000800858.2
First in ClinVar: Aug 05, 2018 Last updated: Jan 26, 2024 |
Comment:
PP4, PM3_very_strong, PS3, PVS1
Number of individuals with the variant: 7
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Pathogenic
(Oct 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021165.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245684.20
First in ClinVar: May 09, 2020 Last updated: Apr 15, 2024 |
Comment:
GAA: PM3:Very Strong, PVS1, PM2, PS3:Moderate
Number of individuals with the variant: 2
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Pathogenic
(Dec 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001193835.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
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 … (more)
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 (less)
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Pathogenic
(Feb 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease II
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448872.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Aug 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321684.8
First in ClinVar: Mar 24, 2015 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000626617.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Dec 01, 1994)
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no assertion criteria provided
Method: literature only
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GLYCOGEN STORAGE DISEASE II
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024414.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2017 |
Comment on evidence:
In a girl with the juvenile form of Pompe disease (GSD2; 232300), Hermans et al. (1994) identified compound heterozygosity for 2 mutations in the GAA … (more)
In a girl with the juvenile form of Pompe disease (GSD2; 232300), Hermans et al. (1994) identified compound heterozygosity for 2 mutations in the GAA gene: P545L (606800.0013) and a 1-bp deletion (525delT), resulting in premature termination of the protein at nucleotide positions 658 to 660. Kroos et al. (1995) reported that although the 525delT mutation was equally frequent (0.11 to 0.16) in all clinical forms of glycogen storage disease II, all 5 patients homozygous for this mutation had the infantile form with less than 1% GAA activity. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Glycogen storage disease type II
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453587.1
First in ClinVar: Jan 01, 2021 Last updated: Jan 01, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000086730.3
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Pompe Disease. | Adam MP | - | 2023 | PMID: 20301438 |
Development of a clinically validated in vitro functional assay to assess pathogenicity of novel GAA variants in patients with Pompe disease identified via newborn screening. | Goomber S | Frontiers in genetics | 2022 | PMID: 36246652 |
Newborn Screening for Pompe Disease: Pennsylvania Experience. | Ficicioglu C | International journal of neonatal screening | 2020 | PMID: 33202836 |
Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness. | Töpf A | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32528171 |
Late-onset Pompe disease associated with polyneuropathy. | Lamartine S Monteiro M | Neuromuscular disorders : NMD | 2019 | PMID: 31676142 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease. | Kishnani PS | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31086307 |
Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. | Nallamilli BRR | Annals of clinical and translational neurology | 2018 | PMID: 30564623 |
Pompe disease treatment with twice a week high dose alglucoside alfa in a patient with severe dilated cardiomyopathy. | Landis JL | Molecular genetics and metabolism reports | 2018 | PMID: 29946513 |
Long-term follow-up of 17 patients with childhood Pompe disease treated with enzyme replacement therapy. | van der Meijden JC | Journal of inherited metabolic disease | 2018 | PMID: 29556838 |
Long term clinical history of an Italian cohort of infantile onset Pompe disease treated with enzyme replacement therapy. | Parini R | Orphanet journal of rare diseases | 2018 | PMID: 29422078 |
Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness. | Johnson K | Orphanet journal of rare diseases | 2017 | PMID: 29149851 |
Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T>G "late-onset" GAA variant. | Rairikar MV | Molecular genetics and metabolism | 2017 | PMID: 28951071 |
Swallow Prognosis and Follow-Up Protocol in Infantile Onset Pompe Disease. | Swift G | JIMD reports | 2017 | PMID: 27344650 |
Severe Cardiomyopathy as the Isolated Presenting Feature in an Adult with Late-Onset Pompe Disease: A Case Report. | Mori M | JIMD reports | 2017 | PMID: 27142047 |
Multidisciplinary care allowing uneventful vaginal delivery in a woman with Pompe disease. | Perniconi B | Neuromuscular disorders : NMD | 2016 | PMID: 27460347 |
Childhood Pompe disease: clinical spectrum and genotype in 31 patients. | van Capelle CI | Orphanet journal of rare diseases | 2016 | PMID: 27189384 |
Response of 33 UK patients with infantile-onset Pompe disease to enzyme replacement therapy. | Broomfield A | Journal of inherited metabolic disease | 2016 | PMID: 26497565 |
Identification and characterization of aberrant GAA pre-mRNA splicing in pompe disease using a generic approach. | Bergsma AJ | Human mutation | 2015 | PMID: 25243733 |
Pearls & Oy-sters: clues to the diagnosis of adult-onset acid maltase deficiency. | Beltran Papsdorf TB | Neurology | 2014 | PMID: 24590251 |
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. | Remiche G | Journal of neurology | 2014 | PMID: 24158270 |
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
Unusual cardiac "masses" in a newborn with infantile pompe disease. | Swarr DT | JIMD reports | 2012 | PMID: 23430912 |
Remarkably low fibroblast acid α-glucosidase activity in three adults with Pompe disease. | Wens SC | Molecular genetics and metabolism | 2012 | PMID: 23000108 |
Trunk muscle involvement in late-onset Pompe disease: study of thirty patients. | Alejaldre A | Neuromuscular disorders : NMD | 2012 | PMID: 22980766 |
A cross-sectional single-centre study on the spectrum of Pompe disease, German patients: molecular analysis of the GAA gene, manifestation and genotype-phenotype correlations. | Herzog A | Orphanet journal of rare diseases | 2012 | PMID: 22676651 |
Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience. | Bali DS | American journal of medical genetics. Part C, Seminars in medical genetics | 2012 | PMID: 22252923 |
Pompe disease: design, methodology, and early findings from the Pompe Registry. | Byrne BJ | Molecular genetics and metabolism | 2011 | PMID: 21439876 |
Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
Pompe disease in a Brazilian series: clinical and molecular analyses with identification of nine new mutations. | Oba-Shinjo SM | Journal of neurology | 2009 | PMID: 19588081 |
Molecular diagnosis of German patients with late-onset glycogen storage disease type II. | Joshi PR | Journal of inherited metabolic disease | 2008 | PMID: 18607768 |
Molecular and functional characterization of eight novel GAA mutations in Italian infants with Pompe disease. | Pittis MG | Human mutation | 2008 | PMID: 18429042 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
Development of a clinical assay for detection of GAA mutations and characterization of the GAA mutation spectrum in a Canadian cohort of individuals with glycogen storage disease, type II. | McCready ME | Molecular genetics and metabolism | 2007 | PMID: 17723315 |
Pompe disease (glycogen storage disease type II) in Argentineans: clinical manifestations and identification of 9 novel mutations. | Palmer RE | Neuromuscular disorders : NMD | 2007 | PMID: 17056254 |
Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II. | Montalvo AL | Human mutation | 2006 | PMID: 16917947 |
Pompe disease diagnosis and management guideline. | Kishnani PS | Genetics in medicine : official journal of the American College of Medical Genetics | 2006 | PMID: 16702877 |
Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II. | Hermans MM | Human mutation | 2004 | PMID: 14695532 |
Identification of four novel mutations in the alpha glucosidase gene in five Italian patients with infantile onset glycogen storage disease type II. | Pittis MG | American journal of medical genetics. Part A | 2003 | PMID: 12923862 |
Frequency of mutations for glycogen storage disease type II in different populations: the delta525T and deltaexon 18 mutations are not generally "common" in white populations. | Hirschhorn R | Journal of medical genetics | 1999 | PMID: 9950376 |
Two extremes of the clinical spectrum of glycogen storage disease type II in one family: a matter of genotype. | Kroos MA | Human mutation | 1997 | PMID: 8990003 |
Glycogen storage disease type II: frequency of three common mutant alleles and their associated clinical phenotypes studied in 121 patients. | Kroos MA | Journal of medical genetics | 1995 | PMID: 8558570 |
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. | Hermans MM | Human molecular genetics | 1994 | PMID: 7881422 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GAA | - | - | - | - |
http://www.pompevariantdatabase.nl/ | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1efdd949-f073-4f5f-b727-fef5720f127f | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/254faa15-f83f-41e6-ab21-e08061aa33a7 | - | - | - | - |
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Text-mined citations for rs386834235 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.