ClinVar Genomic variation as it relates to human health
NM_000642.3(AGL):c.1384del (p.Trp461_Val462insTer)
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.1384del (p.Trp461_Val462insTer)
Variation ID: 189080 Accession: VCV000189080.16
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 1p21.2 1: 99876556 (GRCh38) [ NCBI UCSC ] 1: 100342112 (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 Mar 29, 2015 Apr 20, 2024 Dec 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000642.3:c.1384del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000633.2:p.Trp461_Val462insTer nonsense NM_000642.3:c.1384delG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
nonsense NM_000028.3:c.1384delG NP_000019.2:p.Val462Terfs frameshift nonsense NM_000642.2:c.1384del NM_000643.3:c.1384delG NP_000634.2:p.Val462Terfs frameshift nonsense NM_000644.3:c.1384delG NP_000635.2:p.Val462Terfs frameshift nonsense NM_000646.3:c.1336delG NP_000637.2:p.Val446Terfs frameshift nonsense NM_001425325.1:c.1384delG NP_001412254.1:p.Val462Terfs frameshift nonsense NM_001425326.1:c.1384delG NP_001412255.1:p.Val462Terfs frameshift nonsense NM_001425327.1:c.1183delG NP_001412256.1:p.Val395Terfs frameshift nonsense NM_001425328.1:c.1180delG NP_001412257.1:p.Val394Terfs frameshift nonsense NM_001425329.1:c.1180delG NP_001412258.1:p.Val394Terfs frameshift nonsense NM_001425332.1:c.1006delG NP_001412261.1:p.Val336Terfs frameshift nonsense NC_000001.11:g.99876558del NC_000001.10:g.100342114del NG_012865.1:g.31475del - Protein change
- Other names
- NM_000642.3(AGL):c.1384del
- p.Trp461_Val462insTer
- Canonical SPDI
- NC_000001.11:99876555:GGG:GG
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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.
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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
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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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AGL | - | - |
GRCh38 GRCh37 |
2646 | 2665 |
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
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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 (9) |
criteria provided, multiple submitters, no conflicts
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Dec 11, 2023 | RCV000169486.18 |
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
(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: SCV002055477.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Likely pathogenic
(Dec 09, 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: SCV000220939.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Jul 06, 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: SCV004212937.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 11, 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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Invitae
Accession: SCV000818823.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val462*) 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.Val462*) 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 (rs786204678, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with glycogen storage disease, type III (GSD III) (PMID: 20648714). ClinVar contains an entry for this variant (Variation ID: 189080). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 15, 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: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848479.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Val462X variant in AGL has been reported in the homozygous state in 2 Latino individuals with glycogen storage disease, type III (Goldstein 2010, PMID: … (more)
The p.Val462X variant in AGL has been reported in the homozygous state in 2 Latino individuals with glycogen storage disease, type III (Goldstein 2010, PMID: 20648714). It was also identified in the homozygous state through WGS by the Broad Institute Rare Genomes Project in an adult male with slowly progressive, childhood-onset muscle weakness, elevated CK, and abnormal muscle biopsy with features suggestive of possible lysosomal storage disease. This variant has been identified in 0.003% (1/34582) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant has been reported in ClinVar as pathogenic and likely pathogenic by multiple labs (Variation ID 189080). This nonsense variant leads to a premature termination codon at position 462, which is predicted to lead to a truncated or absent protein. Loss of function of the AGL gene is an established disease mechanism in autosomal recessive glycogen storage disease, type III. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive glycogen storage disease, type III. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Suppporting. (less)
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Pathogenic
(Nov 30, 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: SCV000916429.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: AGL c.1384delG (p.Val462X) 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.1384delG (p.Val462X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Trp680X, p.Arg864X, p.Arg977X). The variant allele was found at a frequency of 4.1e-06 in 245906 control chromosomes (gnomAD). c.1384delG has been reported in the literature in homozygous individuals affected with Glycogen Storage Disease Type III (Golstein_2010). 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. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 26, 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: SCV002783930.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 25, 2023)
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criteria provided, single submitter
Method: curation
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Glycogen storage disease type III
(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: SCV003761286.2
First in ClinVar: Feb 07, 2023 Last updated: Nov 11, 2023 |
Comment:
The homozygous p.Trp461_Val462insTer variant in AGL was identified by our study in one individual with congenital myopathy (Broad Institute Rare Genomes Project). The p.Trp461_Val462insTer variant … (more)
The homozygous p.Trp461_Val462insTer variant in AGL was identified by our study in one individual with congenital myopathy (Broad Institute Rare Genomes Project). The p.Trp461_Val462insTer variant in AGL has been previously reported in 3 unrelated individuals with glycogen storage disease type III (PMID: 34649782, PMID: 20648714) but has been identified in 0.002% (1/34582) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1383849192). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. These three affected individuals (PMID: 34649782, PMID: 20648714) were homozygotes, which increases the likelihood that the p.Trp461_Val462insTer variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 189080) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 461 and leads to a premature termination codon 1 amino acid downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the AGL gene is an established disease mechanism in autosomal recessive glycogen storage disease type III. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive glycogen storage disease type III. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3 (Richards 2015). (less)
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Pathogenic
(Sep 16, 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: SCV001454507.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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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 |
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 |
Text-mined citations for rs786204678 ...
HelpRecord last updated Apr 20, 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.