ClinVar Genomic variation as it relates to human health
NM_000642.3(AGL):c.4260-12A>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_000642.3(AGL):c.4260-12A>G
Variation ID: 1099 Accession: VCV000001099.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p21.2 1: 99916398 (GRCh38) [ NCBI UCSC ] 1: 100381954 (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 Apr 4, 2013 Jun 17, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000642.3:c.4260-12A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_000028.3:c.4260-12A>G intron variant NM_000643.3:c.4260-12A>G intron variant NM_000644.3:c.4260-12A>G intron variant NM_000646.3:c.4212-12A>G intron variant NM_001425325.1:c.4260-12A>G intron variant NM_001425326.1:c.4239-12A>G intron variant NM_001425327.1:c.4059-12A>G intron variant NM_001425328.1:c.4056-12A>G intron variant NM_001425329.1:c.3921-12A>G intron variant NM_001425332.1:c.3882-12A>G intron variant NC_000001.11:g.99916398A>G NC_000001.10:g.100381954A>G NG_012865.1:g.71315A>G - Protein change
- Other names
- IVS32AS, A-G, -12
- Canonical SPDI
- NC_000001.11:99916397:A: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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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AGL | - | - |
GRCh38 GRCh37 |
2675 | 2695 |
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 (1) |
no assertion criteria provided
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Jan 1, 2000 | RCV000001158.3 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2000 | RCV000001157.3 | |
Pathogenic/Likely pathogenic (11) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV000020379.31 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 6, 2023 | RCV000675344.8 | |
AGL-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Feb 10, 2023 | RCV003407251.5 |
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 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease type III
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362038.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: AGL c.4260-12A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: AGL c.4260-12A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3 acceptor site. Three predict the variant creates a cryptic 3 acceptor site. At least two publication reports this variant created a new 3' splice site and resulted in insertion of an 11-bp intron sequence between exon 32 and exon 33 in the patients debrancher mRNA. The predicted mutant enzyme was truncated by 112 amino acids as a result of premature termination (p.Phe1420Hisfs*16) (Okubo_1998, Shaiu_2000). The variant allele was found at a frequency of 5.8e-05 in 243346 control chromosomes (gnomAD). c.4260-12A>G has been reported in the literature in multiple individuals in compound heterozygous or homozygous states affected with Glycogen Storage Disease Type III (Okubo_1998, Shaiu_2000, Lu_2016, Sentner_2012). These data indicate that the variant is very likely to be associated with disease. At least two publication reports this variant had an impact on protein function and debrancher activity in a liver specimen was reduced to less than 30% of the control value (Okubo_1998, Shaiu_2000). Two ClinVar submitters (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
(Jul 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease type III
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556779.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
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Likely pathogenic
(Sep 30, 2014)
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criteria provided, single submitter
Method: literature only
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Glycogen storage disease type III
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220759.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Jan 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease type III
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002778005.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Apr 06, 2023)
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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: SCV004168970.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
Comment:
Published functional studies demonstrate a damaging effect (Okubo et al., 1998); In silico analysis supports a deleterious effect on splicing; This variant is associated with … (more)
Published functional studies demonstrate a damaging effect (Okubo et al., 1998); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 9490286, 33763395, 31589614, 34820282, 25827695) (less)
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Pathogenic
(Jun 13, 2014)
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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: SCV000229533.5
First in ClinVar: Jun 28, 2015 Last updated: Aug 05, 2018 |
Sex: mixed
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Likely pathogenic
(May 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease type III
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001623484.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Sex: mixed
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Pathogenic
(Feb 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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AGL-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004109165.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The AGL c.4260-12A>G variant is predicted to interfere with splicing. This variant has been reported, homozygous, in four families with multiple affected individuals with glycogen … (more)
The AGL c.4260-12A>G variant is predicted to interfere with splicing. This variant has been reported, homozygous, in four families with multiple affected individuals with glycogen storage disease type 3 (GSD III). Haplotype analysis showed that this variant is a founder mutation in Saudia Arabia and cDNA sequence analysis showed that it leads to a truncated protein (Basit et al. 2014. PubMed ID: 25827695). It’s also been reported in the homozygous and compound heterozygous state in multiple unrelated patients, including one patient who showed excessive accumulation of glycogen in the liver (Okubo et al. 1998. PubMed ID: 9490286, Hijazi et al. 2021. PubMed ID: 34820282, Table S1 - Fang et al. 2021. PubMed ID: 33763395). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-100381954-A-G). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jun 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease type III
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004235534.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 20, 2024)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease type III
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000626749.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 31 of the AGL gene. It does not directly change the encoded amino acid sequence of the AGL protein. … (more)
This sequence change falls in intron 31 of the AGL gene. It does not directly change the encoded amino acid sequence of the AGL protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs369973784, gnomAD 0.02%). This variant has been observed in individuals with glycogen storage disease type III (GSDIII) (PMID: 9490286, 10655153, 11924557, 20648714, 22089644, 23430490, 25827695). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS32-12A>G. ClinVar contains an entry for this variant (Variation ID: 1099). Studies have shown that this variant results in 11 nucleotide insertion and introduces a premature termination codon (PMID: 9490286). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease type III
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805787.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Mar 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease type III
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001162837.2
First in ClinVar: Mar 01, 2020 Last updated: Jun 17, 2024 |
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Pathogenic
(Jan 01, 2000)
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no assertion criteria provided
Method: literature only
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GLYCOGEN STORAGE DISEASE, TYPE IIIb
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021307.2
First in ClinVar: Apr 04, 2013 Last updated: May 05, 2014 |
Comment on evidence:
In a 31-year-old Japanese female with GSD type IIIb (GSD3B; 232400), Okubo et al. (1998) detected a homozygous A-to-G transition in the AGL gene 12 … (more)
In a 31-year-old Japanese female with GSD type IIIb (GSD3B; 232400), Okubo et al. (1998) detected a homozygous A-to-G transition in the AGL gene 12 bp upstream of exon 33 that caused activation of a cryptic splice site and insertion of an extra 11 bp of intronic sequence between exons 32 and 33. The mutation was predicted to change the last 15 consecutive C-terminal amino acids before premature termination at codon 1436 and loss of 112 terminal amino acids. The patient's parents were first cousins. Shaiu et al. (2000) identified this mutation in homozygosity in a GSD type IIIa (GSD3A; 232400) Caucasian patient presenting with mild clinical symptoms. They found that the IVS32-12A-G mutation had an allelic frequency of about 5.5% in the GSD III patients tested. (less)
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Pathogenic
(Jan 01, 2000)
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no assertion criteria provided
Method: literature only
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GLYCOGEN STORAGE DISEASE, TYPE IIIa
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021308.2
First in ClinVar: Apr 04, 2013 Last updated: May 05, 2014 |
Comment on evidence:
In a 31-year-old Japanese female with GSD type IIIb (GSD3B; 232400), Okubo et al. (1998) detected a homozygous A-to-G transition in the AGL gene 12 … (more)
In a 31-year-old Japanese female with GSD type IIIb (GSD3B; 232400), Okubo et al. (1998) detected a homozygous A-to-G transition in the AGL gene 12 bp upstream of exon 33 that caused activation of a cryptic splice site and insertion of an extra 11 bp of intronic sequence between exons 32 and 33. The mutation was predicted to change the last 15 consecutive C-terminal amino acids before premature termination at codon 1436 and loss of 112 terminal amino acids. The patient's parents were first cousins. Shaiu et al. (2000) identified this mutation in homozygosity in a GSD type IIIa (GSD3A; 232400) Caucasian patient presenting with mild clinical symptoms. They found that the IVS32-12A-G mutation had an allelic frequency of about 5.5% in the GSD III patients tested. (less)
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Pathogenic
(Jan 09, 2018)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000801010.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Jul 20, 2020)
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no assertion criteria provided
Method: clinical testing
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Glycogen storage disease type III
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002094577.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Glycogen storage disease type III
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000055699.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Associated with milder phenotype
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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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Glycogen Storage Disease Type III. | Adam MP | - | 2022 | PMID: 20301788 |
Spectrum of AGL mutations in Chinese patients with glycogen storage disease type III: identification of 31 novel mutations. | Lu C | Journal of human genetics | 2016 | PMID: 26984562 |
A founder splice site mutation underlies glycogen storage disease type 3 in consanguineous Saudi families. | Basit S | Annals of Saudi medicine | 2014 | PMID: 25827695 |
Mutation Analysis in Glycogen Storage Disease Type III Patients in the Netherlands: Novel Genotype-Phenotype Relationships and Five Novel Mutations in the AGL Gene. | Sentner CP | JIMD reports | 2013 | PMID: 23430490 |
Molecular and biochemical characterization of Tunisian patients with glycogen storage disease type III. | Mili A | Journal of human genetics | 2012 | PMID: 22089644 |
Molecular analysis of the AGL gene: identification of 25 novel mutations and evidence of genetic heterogeneity in patients with Glycogen Storage Disease Type III. | Goldstein JL | Genetics in medicine : official journal of the American College of Medical Genetics | 2010 | PMID: 20648714 |
Mutational and haplotype analysis of AGL in patients with glycogen storage disease type III. | Horinishi A | Journal of human genetics | 2002 | PMID: 11924557 |
Novel mutations in two Japanese cases of glycogen storage disease type IIIa and a review of the literature of the molecular basis of glycogen storage disease type III. | Fukuda T | Journal of inherited metabolic disease | 2000 | PMID: 10801050 |
Genotype-phenotype correlation in two frequent mutations and mutation update in type III glycogen storage disease. | Shaiu WL | Molecular genetics and metabolism | 2000 | PMID: 10655153 |
A novel point mutation in an acceptor splice site of intron 32 (IVS32 A-12-->G) but no exon 3 mutations in the glycogen debranching enzyme gene in a homozygous patient with glycogen storage disease type IIIb. | Okubo M | Human genetics | 1998 | PMID: 9490286 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=AGL | - | - | - | - |
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Text-mined citations for rs369973784 ...
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.