ClinVar Genomic variation as it relates to human health
NM_000642.3(AGL):c.2039G>A (p.Trp680Ter)
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.2039G>A (p.Trp680Ter)
Variation ID: 1096 Accession: VCV000001096.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p21.2 1: 99881329 (GRCh38) [ NCBI UCSC ] 1: 100346885 (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 Oct 8, 2024 Sep 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000642.3:c.2039G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000633.2:p.Trp680Ter nonsense NM_000028.3:c.2039G>A NP_000019.2:p.Trp680Ter nonsense NM_000643.3:c.2039G>A NP_000634.2:p.Trp680Ter nonsense NM_000644.3:c.2039G>A NP_000635.2:p.Trp680Ter nonsense NM_000646.3:c.1991G>A NP_000637.2:p.Trp664Ter nonsense NM_001425325.1:c.2039G>A NP_001412254.1:p.Trp680Ter nonsense NM_001425326.1:c.2039G>A NP_001412255.1:p.Trp680Ter nonsense NM_001425327.1:c.1838G>A NP_001412256.1:p.Trp613Ter nonsense NM_001425328.1:c.1835G>A NP_001412257.1:p.Trp612Ter nonsense NM_001425329.1:c.1835G>A NP_001412258.1:p.Trp612Ter nonsense NM_001425332.1:c.1661G>A NP_001412261.1:p.Trp554Ter nonsense NC_000001.11:g.99881329G>A NC_000001.10:g.100346885G>A NG_012865.1:g.36246G>A - Protein change
- W680*, W664*, W554*, W612*, W613*
- Other names
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- Canonical SPDI
- NC_000001.11:99881328: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 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
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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
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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
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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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Jul 15, 1996 | RCV000001154.3 | |
Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Mar 14, 2024 | RCV000020375.27 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 26, 2024 | RCV000578784.7 |
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
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
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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
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
(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: SCV000226440.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jun 09, 2020)
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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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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001429967.1
First in ClinVar: Aug 21, 2020 Last updated: Aug 21, 2020 |
Clinical Features:
Cirrhosis of liver (present) , Hepatocellular carcinoma (present) , Abnormal hepatic glycogen storage (present)
Sex: female
Tissue: blood
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Likely pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease type III
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001441057.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Pathogenic
(Jun 23, 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:
germline
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Revvity Omics, Revvity
Accession: SCV003816675.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 26, 2024)
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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: SCV000680765.3
First in ClinVar: Feb 13, 2018 Last updated: Oct 08, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 8755644, 23430490, 34820282) (less)
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Pathogenic
(Jan 11, 2018)
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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: SCV000918401.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The AGL c.2039G>A (p.Trp680X) variant results in a premature termination codon, predicted to cause a truncated or absent AGL protein due to nonsense … (more)
Variant summary: The AGL c.2039G>A (p.Trp680X) variant results in a premature termination codon, predicted to cause a truncated or absent AGL protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory (c.2929C>T, p.Arg977X). One in silico tool predicts a damaging outcome for this variant. One functional study showed no GSD residual activity in GSD IIIa patients homozygous for this variant in leukocytes, fibroblasts, and/or liver tissue, and/or muscle tissue (Sentner_2012). This variant was found in 2/245574 control chromosomes in gnomAD at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic AGL variant (0.0022822).This variant has been reported in 4 homozygous patients of Caribbean origin with GSD IIIa (Sentner_2012) and also in one patient diagnosed with GSD type IIIb in compound heterozygosity with AGL c.16C>T (p.Gln6Ter)( Shen_AGL_JCI_1996). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jul 15, 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: SCV002055483.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Pathogenic
(Feb 09, 2022)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501967.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Dec 27, 2021)
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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: SCV002794202.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001224259.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp680*) in the AGL gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Trp680*) in the AGL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). This variant is present in population databases (rs113994129, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease type III (GSDIII) (PMID: 8755644, 23430490). ClinVar contains an entry for this variant (Variation ID: 1096). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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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: SCV004214487.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jul 15, 1996)
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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: SCV000021304.2
First in ClinVar: Apr 04, 2013 Last updated: May 05, 2014 |
Comment on evidence:
In a 41-year-old patient with hepatic glycogen storage disease type III (GSD3B; 232400), but with no clinical or laboratory evidence of myopathy or cardiomyopathy, Shen … (more)
In a 41-year-old patient with hepatic glycogen storage disease type III (GSD3B; 232400), but with no clinical or laboratory evidence of myopathy or cardiomyopathy, Shen et al. (1996) demonstrated compound heterozygosity for 2 mutations in the AGL gene: a 2039G-A transition, resulting in a trp680-to-ter (W680X) substitution, and Q6X (610860.0002). (less)
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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: SCV000040763.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
2039G>A, 2590C>T and 3682C>T are 3 common variants that together account for approximately 28% of pathogenic variants in persons of European origin.
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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 |
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 |
Distinct mutations in the glycogen debranching enzyme found in glycogen storage disease type III lead to impairment in diverse cellular functions. | Cheng A | Human molecular genetics | 2009 | PMID: 19299494 |
Glycogen storage disease type III-hepatocellular carcinoma a long-term complication? | Demo E | Journal of hepatology | 2007 | PMID: 17196294 |
Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle. | Shen J | The Journal of clinical investigation | 1996 | PMID: 8755644 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=AGL | - | - | - | - |
Text-mined citations for rs113994129 ...
HelpRecord last updated Oct 08, 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.