ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.1411_1414del (p.Glu471fs)
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.1411_1414del (p.Glu471fs)
Variation ID: 188874 Accession: VCV000188874.18
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 17q25.3 17: 80110029-80110032 (GRCh38) [ NCBI UCSC ] 17: 78083828-78083831 (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 Mar 29, 2015 Feb 14, 2024 Oct 8, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5(GAA):c.1411_1414del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000152.5:c.1411_1414del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Glu471fs frameshift NM_000152.5:c.1411_1414delGAGA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000152.3:c.1411_1414del NM_000152.4(GAA):c.1411_1414delGAGA NM_001079803.3:c.1411_1414del NP_001073271.1:p.Glu471fs frameshift NM_001079804.3:c.1411_1414del NP_001073272.1:p.Glu471fs frameshift NC_000017.11:g.80110029_80110032del NC_000017.10:g.78083828_78083831del NG_009822.1:g.13474_13477del LRG_673:g.13474_13477del LRG_673t1:c.1411_1414del - Protein change
- E471fs
- Other names
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- Canonical SPDI
- NC_000017.11:80110028:GAGA:
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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.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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
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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 |
2767 | 2817 |
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 (8) |
reviewed by expert panel
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Oct 8, 2020 | RCV000169228.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 29, 2019 | RCV001781522.5 |
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
(Oct 08, 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: SCV001443324.1 First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
This variant, c.1411_1414del (p.Glu471ProfsTer5), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene … (more)
This variant, c.1411_1414del (p.Glu471ProfsTer5), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002513 in the East Asian population, meeting PM2. This variant has been reported multiple times in Asian patients with Pompe disease presenting clinically and identified by newborn screening. At least eight patients with Pompe disease and meeting the ClinGen LSD VCEP's specifications for PP4 have been reported as compound heterozygous with either c.214C>A (p.Leu141Met), c.872T>C, (p.Leu291Pro), c.1933G>C (p.Asp645His), or c.1935C>A (p.Asp645Glu) (PMIDs 8604985, 18458862, 24243590, 31510962). The in trans data for these patients will be used in the assessment of the missense variants and, therefore, was not included here in order to avoid circular logic. Additional patients with this variant have been reported but were not included because no residual GAA activity provided and, therefore, PP4 could not be assessed (PMIDs 10338092, 25466677, 27183828, 27692865, 28394184, 29122469), or pseudodeficiency alleles are present (PMID 19948615, 21232767, 23632029, 27183828). Of note, the variant has been reported to be in cis with two missense changes, c.[752C>T; 761C>T] (p.[Ser251Leu; Ser254Leu]) (PMIDs 20080426, 25466677, 27183828, 29122469). There is a ClinVar entry for this variant (Variation ID: 188874, 2 star review status) with three submitters classifying the variant as pathogenic, and one as likely 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, PP4. (less)
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Pathogenic
(Oct 24, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362547.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: GAA c.1411_1414delGAGA (p.Glu471ProfsX5) 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.1411_1414delGAGA (p.Glu471ProfsX5) 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. The variant allele was found at a frequency of 1.6e-05 in 249358 control chromosomes (gnomAD). c.1411_1414delGAGA has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). The variant has predominantly associated with infantile onset of the disease (e.g. Chien_2006, Labrousse_2010, Shieh_1996, Wan_2008). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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: SCV001423056.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Glu471ProfsTer5 variant in GAA has been reported in 13 individuals from China or Taiwan with Glycogen Storage Disease II (PMID: 28394184, 18458862, 19948615, 10338092, … (more)
The p.Glu471ProfsTer5 variant in GAA has been reported in 13 individuals from China or Taiwan with Glycogen Storage Disease II (PMID: 28394184, 18458862, 19948615, 10338092, 8604985), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 188874). This variant has been identified in 0.025% (5/19900) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770276275). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 471 and leads to a premature termination codon 5 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. The presence of this variant in combination with reported pathogenic and likely pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Glu471ProfsTer5 variant is pathogenic (PMID: 18458862, 19948615, 28394184; Variation ID: 189006, 4029). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected by assays with patient fibroblasts and/or lymphocytes (PMID: 18458862, 19948615, 28394184). 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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Likely pathogenic
(Jul 09, 2014)
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criteria provided, single submitter
Method: literature only
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Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220494.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Mar 19, 2022)
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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: SCV002793115.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 06, 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: SCV004197862.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 29, 2019)
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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: SCV002023793.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 03, 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:
germline
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Invitae
Accession: SCV001209354.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu471Profs*5) 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.Glu471Profs*5) 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 (rs770276275, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with infantile-onset Pompe disease (PMID: 8604985, 18458862, 28394184, 29046207). ClinVar contains an entry for this variant (Variation ID: 188874). For these reasons, this variant has been classified as Pathogenic. (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
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Natera, Inc.
Accession: SCV001455615.1
First in ClinVar: Jan 01, 2021 Last updated: Jan 01, 2021 |
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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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Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease. | Mori M | Molecular genetics and metabolism | 2017 | PMID: 29122469 |
[Clinical characteristics and GAA gene mutation in children with glycogen storage disease type II: an analysis of 3 cases]. | Yuan S | Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics | 2017 | PMID: 29046207 |
Clinical and Molecular Characterization of Infantile-Onset Pompe Disease in Mainland Chinese Patients: Identification of Two Common Mutations. | Chen X | Genetic testing and molecular biomarkers | 2017 | PMID: 28394184 |
Long-term prognosis of patients with infantile-onset Pompe disease diagnosed by newborn screening and treated since birth. | Chien YH | The Journal of pediatrics | 2015 | PMID: 25466677 |
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 |
Genetic heterozygosity and pseudodeficiency in the Pompe disease newborn screening pilot program. | Labrousse P | Molecular genetics and metabolism | 2010 | PMID: 20080426 |
Pompe disease in infants: improving the prognosis by newborn screening and early treatment. | Chien YH | Pediatrics | 2009 | PMID: 19948615 |
Identification of eight novel mutations of the acid alpha-glucosidase gene causing the infantile or juvenile form of glycogen storage disease type II. | Wan L | Journal of neurology | 2008 | PMID: 18458862 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
Brain development in infantile-onset Pompe disease treated by enzyme replacement therapy. | Chien YH | Pediatric research | 2006 | PMID: 16857770 |
Molecular genetic study of Pompe disease in Chinese patients in Taiwan. | Ko TM | Human mutation | 1999 | PMID: 10338092 |
Identification of a small deletion in one allele of patients with infantile form of glycogen storage disease type II. | Shieh JJ | Biochemical and biophysical research communications | 1996 | PMID: 8604985 |
Human lysosomal alpha-glucosidase. Characterization of the catalytic site. | Hermans MM | The Journal of biological chemistry | 1991 | PMID: 1856189 |
Primary structure and processing of lysosomal alpha-glucosidase; homology with the intestinal sucrase-isomaltase complex. | Hoefsloot LH | The EMBO journal | 1988 | PMID: 3049072 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/10ad7071-e185-453a-b600-d23c0c86e52b | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/945730af-c6de-4db4-8be4-afb5df17ff92 | - | - | - | - |
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Text-mined citations for rs770276275 ...
HelpRecord last updated Mar 30, 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.