ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.-32-3C>A
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.-32-3C>A
Variation ID: 371622 Accession: VCV000371622.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80104552 (GRCh38) [ NCBI UCSC ] 17: 78078351 (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 6, 2017 Feb 14, 2024 Nov 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.-32-3C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001079803.3:c.-32-3C>A intron variant NM_001079804.3:c.-32-3C>A intron variant NC_000017.11:g.80104552C>A NC_000017.10:g.78078351C>A NG_009822.1:g.7997C>A LRG_673:g.7997C>A LRG_673t1:c.-32-3C>A - Protein change
- Other names
- NM_000152.4(GAA):c.-32-3C>A
- Canonical SPDI
- NC_000017.11:80104551:C: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 |
2754 | 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 (4) |
reviewed by expert panel
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Nov 21, 2023 | RCV000412452.8 |
Submissions - Germline
Classification
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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
(Nov 21, 2023)
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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: SCV004227906.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The NM_000152.5:c.-32-3C>A variant is located in the splice acceptor region of intron 1 and has been shown to impact splicing. In fibroblasts from an individual … (more)
The NM_000152.5:c.-32-3C>A variant is located in the splice acceptor region of intron 1 and has been shown to impact splicing. In fibroblasts from an individual with Pompe disease who was compound heterozygous for the variant and a missense variant in GAA, RT-PCR revealed loss of exon 2 (p.M1_T182del, which includes the 27 residues of signal sequence, the 42 residues of the propeptide and the first 113 amino acids of the mature protein (from 70 to 182) (PMID: 18429042). A later study, in which the variant was expressed in a minigene, showed that the variant results in about 20% of transcripts with normal splicing of exon 2 (of note, this is a slightly lower level of normal splicing than observed for a well known pathogenic variant in the same splice region, c.-32-13T>G). Abnormal splicing events included complete loss of exon 2 (r.-32_546del) and activation of a cryptic splice site (r.-32_486del) (PMID: 31301153). Due to loss of a critical region (the signal sequence) in aberrantly spliced transcripts, but with presence of some normal transcript (albeit at a lower level than a known pathogenic variant in the same splice region), PVS1 was applied at the strong level (PMID: 37352859) (PVS1_Strong, PS1_Supporting applied based on recommendations in PMID: 37352859). This variant has been reported in at least 6 probands with late onset Pompe disease including two individuals with documented GAA activity <30% normal in fibroblasts (PMID: 19046416, 21550241) (PP4_Moderate). Two of these probands have been reported to have this variant in compound heterozygosity, phase unknown, with another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.1655T>C (p.Leu552Pro) (PMID: 18429042) and c.482_483del (PMID: 21550241). In addition, three affected siblings have been reported to be homozygous for the variant (PMID: 19588081, 20464284, 25681614) (PM3). Another three patients are compound heterozygous for the variant and a missense variant (either c.1905C>A (p.Asn635Lys), c.1447G>A (p.Gly483Arg), or c.2173C>T (p.Arg725Trp)) (PMID: 19588081). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.0. is 0.000007314 (8/1093866 alleles) in the European non-Finnish populationn, 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: 371662). 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 (Specifications Version 2.0): PVS1_Strong, PM3, PS1_Supporting, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 21, 2023). (less)
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Pathogenic
(Mar 09, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500249.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 3' acceptor site. Goina_2019 have shown … (more)
Variant summary: Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 3' acceptor site. Goina_2019 have shown c.-32-3C>A and -32-3C>G results in exon 2 skipping. The variant was absent in 233126 control chromosomes (gnomAD). c.-32-3C>A has been reported in multiple individuals homozygous and compound heterozygous affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and this variant was segregated with disease in at least one family (examples: Oba-Shinjo_2009 and Grzesiuk_2010). The variant also segregated with the disease. These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Nov 02, 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: SCV000487248.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Mar 09, 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: SCV001587691.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 2, and is expected … (more)
For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 2, and is expected to result in the loss of the initiator methionine (PMID: 18429042). ClinVar contains an entry for this variant (Variation ID: 371622). This variant has been observed in individuals with glycogen storage disease type II (PMID: 18429042, 19588081, 20464284). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 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 is likely to result in the loss of the initiator methionine. (less)
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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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Assessment of the functional impact on the pre-mRNA splicing process of 28 nucleotide variants associated with Pompe disease in GAA exon 2 and their recovery using antisense technology. | Goina E | Human mutation | 2019 | PMID: 31301153 |
Homozygotic intronic GAA mutation in three siblings with late-onset Pompe's disease. | Grzesiuk AK | Arquivos de neuro-psiquiatria | 2010 | PMID: 20464284 |
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 and functional characterization of eight novel GAA mutations in Italian infants with Pompe disease. | Pittis MG | Human mutation | 2008 | PMID: 18429042 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/d7050ce4-1aa4-4158-9721-09823c6c79f9 | - | - | - | - |
Text-mined citations for rs1055945806 ...
HelpRecord last updated Feb 14, 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.