ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.1076-22T>G
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.1076-22T>G
Variation ID: 370278 Accession: VCV000370278.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80108467 (GRCh38) [ NCBI UCSC ] 17: 78082266 (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 Jan 7, 2017 Apr 6, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.1076-22T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001079803.3:c.1076-22T>G intron variant NM_001079804.3:c.1076-22T>G intron variant NC_000017.11:g.80108467T>G NC_000017.10:g.78082266T>G NG_009822.1:g.11912T>G LRG_673:g.11912T>G LRG_673t1:c.1076-22T>G - Protein change
- Other names
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- Canonical SPDI
- NC_000017.11:80108466:T:G
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
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 |
2757 | 2807 |
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 (6) |
reviewed by expert panel
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Feb 6, 2024 | RCV000409600.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 20, 2021 | RCV001570177.7 |
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
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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
(Feb 06, 2024)
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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: SCV004809072.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
Comment:
The NM_000152.5:c.1076-22T>G variant in GAA occurs within intron 6. Experimental studies show that the variant causes skipping of biologically-relevant-exon 6 resulting in an in-frame deletion … (more)
The NM_000152.5:c.1076-22T>G variant in GAA occurs within intron 6. Experimental studies show that the variant causes skipping of biologically-relevant-exon 6 resulting in an in-frame deletion of amino acids 319-358 (PMIDs 9259196, 10737124). This includes part of the GAA catalytic barrel (amino acids 347-727) (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837) (PVS1_Strong). At least 7 probands have been reported with this variant, at least 5 of them with reported GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PP4_Moderate). Of these individuals, 6 are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP, including 2 confirmed in trans - c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1) (PMID: 9259196), c.1437+1G>A (ClinVar Variation ID: 555864, SCV004227900.1), and 4 with phase unknown - c.1942G>A (p.Gly648Ser) (ClinVar Variation ID: 188902, SCV001371752.2) (PMID: 25455803), c.-32-13T>G (ClinVar Variation ID: 4027) (PMID: 22613277), c.1841C>A (p.Thr614Lys) (ClinVar Variation ID: 167113, SCV001371751.1) (PMID: 21484825), and c.525delT (ClinVar Variation ID: 4033, SCV001443331.1) (PMID: 29181627). In addition, two siblings are homozygous for the variant (PMID: 10737124) (PM3_VeryStrong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002658 (3/112848 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 370278). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1_Strong, PM3_Strong, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on February 6, 2024). (less)
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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: yes
Allele origin:
germline
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GeneDx
Accession: SCV001794408.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Predicted to create a strong cryptic splice acceptor site upstream of the natural splice acceptor site of intron 6 and analysis of patient cDNA demonstrates … (more)
Predicted to create a strong cryptic splice acceptor site upstream of the natural splice acceptor site of intron 6 and analysis of patient cDNA demonstrates an in-frame insertion of 21 nucleotides and skipping of exon 6 causing insertion of 7 incorrect amino acids and loss of 40 amino acids encoded by exon 6 (Adams et al., 1997; Vorgerd et al., 1998); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31342611, 29181627, 9259196, 22613277, 10737124, 17643989, 21179066, 21484825, 27408821, 22676651, 25455803, 23013746, 9529346) (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: SCV001422619.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The c.1076-22T>G variant in GAA has been reported in 8 individuals (including 3 Germans, 2 Dutch, and 1 African American/Caucasian individuals) with Glycogen Storage Disorder … (more)
The c.1076-22T>G variant in GAA has been reported in 8 individuals (including 3 Germans, 2 Dutch, and 1 African American/Caucasian individuals) with Glycogen Storage Disorder II (PMID: 10737124, 9259196, 25455803, 22613277, 21484825, 22676651, 23013746), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370278). This variant has been identified in 0.003% (3/112848) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762260678). 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 with RNA extracted from individuals homozygous for this variant provide some evidence that the c.1076-22T>G variant may cause abnormal splicing (PMID: 10737124). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact splicing, though this information is not predictive enough to determine pathogenicity. The presence of this variant in the homozygous state and in combination with pathogenic variants, and in individuals with Glycogen Storage Disorder II increases the likelihood that the c.1076-22T>G variant is pathogenic (PMID: 10737124, 22676651, 22613277, 9259196, 21484825). The phenotype of homozygous and heterozygous individuals with this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity detected in relevant tissues (PMID: 10737124, 22676651, 22613277, 9259196, 21484825). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disorder II in an autosomal recessive manner based on in vitro functional studies and multiple occurrences with pathogenic variants. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PP3, PP4 (Richards 2015). (less)
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Likely pathogenic
(Jan 05, 2016)
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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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Counsyl
Accession: SCV000485540.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Mar 30, 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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Baylor Genetics
Accession: SCV004197914.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 20, 2021)
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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: SCV002023834.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 07, 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: SCV001205933.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
Studies have shown that this variant results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 9259196). ClinVar … (more)
Studies have shown that this variant results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 9259196). ClinVar contains an entry for this variant (Variation ID: 370278). This variant is also known as IVS6-22T>G. This variant has been observed in individual(s) with glycogen storage disease type II (GSD II) (PMID: 9259196, 10737124, 22613277). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs762260678, gnomAD 0.003%). This sequence change falls in intron 6 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. 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: SCV001455603.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 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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Muscle ultrasound in classic infantile and adult Pompe disease: a useful screening tool in adults but not in infants. | Vill K | Neuromuscular disorders : NMD | 2015 | PMID: 25455803 |
Effect of enzyme therapy and prognostic factors in 69 adults with Pompe disease: an open-label single-center study. | de Vries JM | Orphanet journal of rare diseases | 2012 | PMID: 23013746 |
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 |
The impact of antibodies in late-onset Pompe disease: a case series and literature review. | Patel TT | Molecular genetics and metabolism | 2012 | PMID: 22613277 |
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 |
Adult-onset glycogen storage disease type II: phenotypic and allelic heterogeneity in German patients. | Vorgerd M | Neurogenetics | 1998 | PMID: 10737124 |
Glycogenosis type II: a juvenile-specific mutation with an unusual splicing pattern and a shared mutation in African Americans. | Adams EM | Human mutation | 1997 | PMID: 9259196 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6c34d3ac-52aa-4054-b9e3-ab95609f4ebe | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f3d7eb07-7a09-404c-9e0f-886bedf428e4 | - | - | - | - |
Text-mined citations for rs762260678 ...
HelpRecord last updated Apr 06, 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.