ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.2237G>A (p.Trp746Ter)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000152.5(GAA):c.2237G>A (p.Trp746Ter)
Variation ID: 280063 Accession: VCV000280063.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80117015 (GRCh38) [ NCBI UCSC ] 17: 78090814 (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 Dec 6, 2016 Jun 17, 2024 May 5, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.2237G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Trp746Ter nonsense NM_001079803.3:c.2237G>A NP_001073271.1:p.Trp746Ter nonsense NM_001079804.3:c.2237G>A NP_001073272.1:p.Trp746Ter nonsense NC_000017.11:g.80117015G>A NC_000017.10:g.78090814G>A NG_009822.1:g.20460G>A LRG_673:g.20460G>A LRG_673t1:c.2237G>A - Protein change
- W746*
- Other names
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- Canonical SPDI
- NC_000017.11:80117014:G:A
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
2797 | 2848 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Jun 14, 2022 | RCV000302789.9 | |
Pathogenic (8) |
reviewed by expert panel
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May 5, 2020 | RCV000501120.23 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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
(May 05, 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
FDA Recognized Database
Accession: SCV001371720.1 First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
This variant, c.2237G>A (p.Trp746Ter), which results in a premature termination codon, is expected to result in nonsense mediated decay and absence of gene product, meeting … (more)
This variant, c.2237G>A (p.Trp746Ter), which results in a premature termination codon, is expected to result in nonsense mediated decay and absence of gene product, meeting PVS1. This is supported by the finding that patients with this variant have no GAA cross-reactive immunological material in protein isolated from skin fibroblast cultures i.e. CRIM-negative (PMID 22252923). The highest population minor allele frequency in gnomAD for this variant is 0.000008834 in the European non-Finnish population, meeting PM2 (<0.001). This variant has been reported in at least 15 patients who also meet the LSD VCEP's PP4 criterion (PMIDs 12923862, 16917947, 17056254, 18285536, 21484825, 22237443, 24158270, 26497565). The c.2237G>A variant was found in compound heterozygosity with c.-32-13T>G in 9 of 40 Italian patients studied; six of these patients meet PP4 and in 4 of those patients the phase was confirmed in trans (PMID 16917947) (4.5 points). Additional patients meeting PP4 have been reported to be compound heterozygous for the variant and c.-32-13T>G, c.2481+110_2646+39del, c.1128_1129delinsC, c.670C>T (p.Arg224Trp), c.853C>T (p.Pro285Ser) (PMIDs 12923862, 17056254, 18285536, 21484825, 22237443); the phase was not confirmed in any of these cases. Four patients meeting PP4 criteria are reported to be homozygous for the variant (PMID 26497565). Four additional patients have been reported with this variant but residual GAA activity was not reported, and therefore PP4 cannot be assessed (PMID 18429042, 24269976). Based on this data, PP4 and PM3_Very Strong are met. There is a ClinVar entry for this variant (Variation ID: 280063; 2 star review status) with 5 submitters all 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
(May 23, 2016)
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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
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Genetic Services Laboratory, University of Chicago
Accession: SCV000594901.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Pathogenic
(Jun 08, 2016)
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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: SCV000329853.5
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The W746X pathogenic variant in the GAA gene has been previously reported multiple times in association with both infantile-onset and late-onset GSDII (Beesley et al., … (more)
The W746X pathogenic variant in the GAA gene has been previously reported multiple times in association with both infantile-onset and late-onset GSDII (Beesley et al., 1998; Montalvo et al., 2006; Pittis et al., 2008). Clinical variability was described amongst individuals harboring the W746X variant and GAA enzyme activity ranged from decreased to absent (Montalvo et al., 2006; Remiche et al., 2014). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W746X nonsense variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. (less)
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Pathogenic
(Jun 13, 2018)
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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: SCV000861727.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Aug 13, 2018)
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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: SCV000917394.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: GAA c.2237G>A (p.Trp746X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: GAA c.2237G>A (p.Trp746X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2560C>T, p.Arg854*). The variant allele was found at a frequency of 8.1e-06 in 245810 control chromosomes (gnomAD). c.2237G>A has been reported in the literature in multiple individuals affected with Late Onset Pompe Disease (Montalvo_2006, Liu_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 22, 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: SCV001422772.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Trp746Ter variant in GAA has been reported in at least 33 individuals (including 15 Italians, 5 from the UK, and 4 Chinese individuals) with … (more)
The p.Trp746Ter variant in GAA has been reported in at least 33 individuals (including 15 Italians, 5 from the UK, and 4 Chinese individuals) with Glycogen Storage Disease II (PMID: 26497565, 10206684, 12923862, 16917947, 18429042, 18285536, 21484825, 22980766, 24158270, 22237443, 24169249, 25488666, 25526786, 24269976, 17056254), and has also been reported pathogenic by GeneDx, UChicago, EGL Genetic Diagnostics, Integrated Genetics, and Invitae in ClinVar (Variation ID: 280063). This variant has been identified in 0.001% (1/113202) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs752921215). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 746, which is 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. The presence of this variant in the homozygous state and in trans with pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp746Ter variant is pathogenic (PMID: 26497565, 16917947). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with reduced GAA activity detected in relevant tissues, consistent with disease (PMID: 26497565, 24158270, 22237443, 21484825, 17056254, 12923862, 18285536, 16917947). Another variant at the same position with the same amino acid change, c.2238G>A (p.Trp746Ter), has been reported as a pathogenic and likely pathogenic variant in association with Glycogen Storage Disease II in ClinVar (Variation ID: 370904). 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_VeryStrong, PM2, PP4 (Richards 2015). (less)
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Pathogenic
(Dec 13, 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: SCV002789737.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 14, 2022)
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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: SCV002021188.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 06, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000752063.6
First in ClinVar: Aug 28, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp746*) 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.Trp746*) 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 (rs752921215, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Pompe disease (PMID: 10206684, 24158270, 25488666). ClinVar contains an entry for this variant (Variation ID: 280063). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 26, 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:
unknown
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Baylor Genetics
Accession: SCV004195420.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Aug 31, 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
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Natera, Inc.
Accession: SCV002092116.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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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Identification of Seven Novel Mutations in the Acid Alpha-glucosidase Gene in Five Chinese Patients with Late-onset Pompe Disease. | Liu HX | Chinese medical journal | 2018 | PMID: 29451150 |
Response of 33 UK patients with infantile-onset Pompe disease to enzyme replacement therapy. | Broomfield A | Journal of inherited metabolic disease | 2016 | PMID: 26497565 |
Pompe disease results in a Golgi-based glycosylation deficit in human induced pluripotent stem cell-derived cardiomyocytes. | Raval KK | The Journal of biological chemistry | 2015 | PMID: 25488666 |
Clinical and GAA gene mutation analysis in mainland Chinese patients with late-onset Pompe disease: identifying c.2238G > C as the most common mutation. | Liu X | BMC medical genetics | 2014 | PMID: 25526786 |
Clinical and molecular genetic study of infantile-onset Pompe disease in Chinese patients: identification of 6 novel mutations. | Fu L | Gene | 2014 | PMID: 24269976 |
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 |
[Clinical features and acid alpha-glucosidase gene mutation in 7 Chinese patients with glycogen storage disease type II]. | Liu Q | Zhonghua yi xue za zhi | 2013 | PMID: 24169249 |
Trunk muscle involvement in late-onset Pompe disease: study of thirty patients. | Alejaldre A | Neuromuscular disorders : NMD | 2012 | PMID: 22980766 |
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 |
Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease. | Messinger YH | Genetics in medicine : official journal of the American College of Medical Genetics | 2012 | PMID: 22237443 |
Molecular analysis and protein processing in late-onset Pompe disease patients with low levels of acid α-glucosidase activity. | Bali DS | Muscle & nerve | 2011 | PMID: 21484825 |
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 |
Molecular pathology and enzyme processing in various phenotypes of acid maltase deficiency. | Nascimbeni AC | Neurology | 2008 | PMID: 18285536 |
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 |
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 |
The identification of five novel mutations in the lysosomal acid a-(1-4) glucosidase gene from patients with glycogen storage disease type II. Mutations in brief no. 134. Online. | Beesley CE | Human mutation | 1998 | PMID: 10206684 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GAA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6b1d795d-e095-4a45-947e-c3f543da6b19 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/d862735d-a0a7-4915-bb07-1954405ec682 | - | - | - | - |
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Text-mined citations for rs752921215 ...
HelpRecord last updated Sep 29, 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.