ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.3G>A (p.Met1Ile)
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.3G>A (p.Met1Ile)
Variation ID: 972816 Accession: VCV000972816.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80104589 (GRCh38) [ NCBI UCSC ] 17: 78078388 (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 Jul 19, 2020 Feb 14, 2024 Oct 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.3G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Met1Ile missense initiator codon variant NM_001079803.3:c.3G>A NP_001073271.1:p.Met1Ile missense initiator codon variant NM_001079804.3:c.3G>A NP_001073272.1:p.Met1Ile missense initiator codon variant NC_000017.11:g.80104589G>A NC_000017.10:g.78078388G>A NG_009822.1:g.8034G>A LRG_673:g.8034G>A - Protein change
- M1I
- Other names
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- Canonical SPDI
- NC_000017.11:80104588: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
- Links
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 28, 2023 | RCV001249078.5 |
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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Likely pathogenic
(Jun 12, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001737739.2
First in ClinVar: Jun 23, 2021 Last updated: Sep 03, 2023 |
Comment:
Variant summary: GAA c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded … (more)
Variant summary: GAA c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream putative in-frame start codon (Methionine) is located at p.Met122 in exon 2 of the GAA gene. The predicted truncated protein loses part of N-terminus of the encoded protein. Loss-of-function variants upstream of p.Met122 have been reported to be associated with Glycogen Storage Disease, Type 2 (example, p.R40*, p.Q115*, HGMD database). The variant allele was found at a frequency of 4e-06 in 247470 control chromosomes. c.3G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and has been subsequently cited by other studies due to authorship/institutional/patient overlap between studies (example, Kroos_2008, Yves Carlier_2011, Bali_2012, Desai_2019, Kishnani_2019, ElMallah_2020). Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, c.1A>G and c.1A>T, have been reported in association with disease in the literature and the HGMD database. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jan 29, 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: SCV001423033.3
First in ClinVar: Jul 19, 2020 Last updated: Sep 03, 2023 |
Comment:
The c.3G>A (p.Met1?) variant in GAA has been reported in at least three individuals with glycogen storage disease (PMID: 21803581, 18425781, 22252923, 22981821), and has … (more)
The c.3G>A (p.Met1?) variant in GAA has been reported in at least three individuals with glycogen storage disease (PMID: 21803581, 18425781, 22252923, 22981821), and has been identified in 0.001% (1/111790) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1187796945). 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 located in the first amino acid of exon two and obliterates the methionine initiation codon. The next in-frame methionine is at amino acid residue 122 and there are at least seven reported pathogenic or likely pathogenic variants in ClinVar between amino acid 1 and amino acid 122. Proteins lacking this region are predicted to be extremely unstable (PMID: 22252923, 30192042, 22644586), suggesting that the c.3G>A variant may result in a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease. In vitro functional studies provide some evidence that the p.Met1? variant may impact protein function (PMID: 18425781). However, these types of assays may not accurately represent biological function. Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, c.1A>G and c.1A>T, have been reported in association with disease in the literature and ClinVar (PMID: 22252923, 30192042, 29889338, 28316933, 22644586; Variation ID: 188785). This variant was reported in combination with known pathogenic variants (VariationID: 4027, PMID: 22981821, 21803581, 22252923) and in individuals with glycogen storage disease. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1_Strong (Richards 2015). (less)
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Pathogenic
(Oct 28, 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: SCV004297574.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects the initiator methionine of the GAA mRNA. The next in-frame methionine is located at codon 122. This variant is present in … (more)
This sequence change affects the initiator methionine of the GAA mRNA. The next in-frame methionine is located at codon 122. This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of the initiator codon has been observed in individual(s) with Pompe disease (PMID: 22252923, 29124014, 29422078, 31086307). ClinVar contains an entry for this variant (Variation ID: 972816). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects GAA function (PMID: 22644586, 31301153). For these reasons, this variant has been classified as Pathogenic. (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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Pulmonary outcome measures in long-term survivors of infantile Pompe disease on enzyme replacement therapy: A case series. | ElMallah MK | Pediatric pulmonology | 2020 | PMID: 31899940 |
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 |
Characterization of immune response in Cross-Reactive Immunological Material (CRIM)-positive infantile Pompe disease patients treated with enzyme replacement therapy. | Desai AK | Molecular genetics and metabolism reports | 2019 | PMID: 31193175 |
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 |
Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study. | Semplicini C | Journal of inherited metabolic disease | 2018 | PMID: 30155607 |
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 |
A molecular analysis of the GAA gene and clinical spectrum in 38 patients with Pompe disease in Japan. | Fukuhara Y | Molecular genetics and metabolism reports | 2017 | PMID: 29124014 |
Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants. | Kroos M | Human mutation | 2012 | PMID: 22644586 |
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 |
Whole-body muscle MRI in 20 patients suffering from late onset Pompe disease: Involvement patterns. | Carlier RY | Neuromuscular disorders : NMD | 2011 | PMID: 21803581 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/d639cae3-356a-4ad3-899c-259f102cf88d | - | - | - | - |
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Text-mined citations for rs1187796945 ...
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.