ClinVar Genomic variation as it relates to human health
NM_000642.3(AGL):c.4459C>T (p.Arg1487Ter)
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.4459C>T (p.Arg1487Ter)
Variation ID: 456508 Accession: VCV000456508.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p21.2 1: 99916709 (GRCh38) [ NCBI UCSC ] 1: 100382265 (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 May 26, 2018 Feb 20, 2024 Jan 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000642.3:c.4459C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000633.2:p.Arg1487Ter nonsense NM_000028.3:c.4459C>T NP_000019.2:p.Arg1487Ter nonsense NM_000643.3:c.4459C>T NP_000634.2:p.Arg1487Ter nonsense NM_000644.3:c.4459C>T NP_000635.2:p.Arg1487Ter nonsense NM_000646.3:c.4411C>T NP_000637.2:p.Arg1471Ter nonsense NM_001425325.1:c.4459C>T NP_001412254.1:p.Arg1487Ter nonsense NM_001425326.1:c.4438C>T NP_001412255.1:p.Arg1480Ter nonsense NM_001425327.1:c.4258C>T NP_001412256.1:p.Arg1420Ter nonsense NM_001425328.1:c.4255C>T NP_001412257.1:p.Arg1419Ter nonsense NM_001425329.1:c.4120C>T NP_001412258.1:p.Arg1374Ter nonsense NM_001425332.1:c.4081C>T NP_001412261.1:p.Arg1361Ter nonsense NC_000001.11:g.99916709C>T NC_000001.10:g.100382265C>T NG_012865.1:g.71626C>T - Protein change
- R1487*, R1471*, R1361*, R1374*, R1419*, R1420*, R1480*
- Other names
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- Canonical SPDI
- NC_000001.11:99916708:C:T
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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 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD) 0.00011
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 |
2635 | 2654 |
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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 7, 2024 | RCV000531434.20 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 10, 2018 | RCV000825508.4 |
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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Likely pathogenic
(Sep 08, 2017)
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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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Counsyl
Accession: SCV000793936.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
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Likely pathogenic
(Jan 10, 2018)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966816.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Arg1487X variant in AGL has been reported in the compound heterozygous sta te in 1 individual with glycogen storage disorder type III (GSDIII; Quackenbush … (more)
The p.Arg1487X variant in AGL has been reported in the compound heterozygous sta te in 1 individual with glycogen storage disorder type III (GSDIII; Quackenbush 2016). It has also been identified in 2/24018 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12118058 ), which is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 1487. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated p rotein. Many other truncating variants, which are also predicted to escape NMD a nd located in this region of the AGL gene, have been reported in affected indivi duals with deficient enzyme activity, suggesting that the carboxy terminus is es sential for normal enzyme function (Parvari 1997, Shen 1997, Rousseau-Nepton 201 5, Lu 2016). In summary, although additional studies are required to fully estab lish its clinical significance, the p.Arg1487X variant is likely pathogenic. ACM G/AMP Criteria applied: PVS1_Strong, PM3, PP4. (less)
Number of individuals with the variant: 1
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Likely 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: SCV002055551.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Likely pathogenic
(Mar 04, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500079.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: AGL c.4459C>T (p.Arg1487X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: AGL c.4459C>T (p.Arg1487X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncation downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.6e-05 in 250906 control chromosomes (gnomAD). c.4459C>T has been reported in the literature in a compound heterozygous individual affected with Glycogen Storage Disease (example: Quackenbush_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified variant as likely pathogenic (n=3), pathogenic (n=2) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Oct 03, 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:
unknown
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Baylor Genetics
Accession: SCV004214542.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 23, 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: SCV002023703.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 07, 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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Invitae
Accession: SCV000626760.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1487*) in the AGL gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg1487*) in the AGL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the AGL protein. This variant is present in population databases (rs12118058, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease type III (PMID: 29374762). ClinVar contains an entry for this variant (Variation ID: 456508). This variant disrupts a region of the AGL protein in which other variant(s) (p.Tyr1510*) have been determined to be pathogenic (PMID: 8990006, 20071996, 20490926, 23430490). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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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Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Late presentation of glycogen storage disease types Ia and III in children with short stature and hepatomegaly. | Quackenbush D | Journal of pediatric endocrinology & metabolism : JPEM | 2018 | PMID: 29374762 |
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 AGL mutation causing glycogen storage disease type IIIa in Inuit identified through whole-exome sequencing: a case series. | Rousseau-Nepton I | CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne | 2015 | PMID: 25602008 |
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 |
Glycogen storage disease type III in the Irish population. | Crushell E | Journal of inherited metabolic disease | 2010 | PMID: 20490926 |
The electrodiagnostic characteristics of Glycogen Storage Disease Type III. | Hobson-Webb LD | Genetics in medicine : official journal of the American College of Medical Genetics | 2010 | PMID: 20071996 |
Elevated serum biotinidase activity in hepatic glycogen storage disorders--a convenient biomarker. | Paesold-Burda P | Journal of inherited metabolic disease | 2007 | PMID: 17994282 |
A single-base deletion in the 3'-coding region of glycogen-debranching enzyme is prevalent in glycogen storage disease type IIIA in a population of North African Jewish patients. | Parvari R | European journal of human genetics : EJHG | 1997 | PMID: 9412782 |
A nonsense mutation due to a single base insertion in the 3'-coding region of glycogen debranching enzyme gene associated with a severe phenotype in a patient with glycogen storage disease type IIIa. | Shen J | Human mutation | 1997 | PMID: 8990006 |
Text-mined citations for rs12118058 ...
HelpRecord last updated Mar 17, 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.