NM_000642.3(AGL):c.294-2A>T AND Glycogen storage disease type III

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Mar 17, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000412181.25

Allele description [Variation Report for NM_000642.3(AGL):c.294-2A>T]

NM_000642.3(AGL):c.294-2A>T

Gene:

AGL:amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p21.2

Genomic location:

Preferred name:

NM_000642.3(AGL):c.294-2A>T

HGVS:

NC_000001.11:g.99862255A>T
NG_012865.1:g.17172A>T
NM_000028.2:c.294-2A>T
NM_000028.3:c.294-2A>T
NM_000642.3:c.294-2A>TMANE SELECT
NM_000643.3:c.294-2A>T
NM_000644.3:c.294-2A>T
NM_000646.3:c.246-2A>T
NM_001425325.1:c.294-2A>T
NM_001425326.1:c.294-2A>T
NM_001425327.1:c.294-2A>T
NM_001425328.1:c.294-2A>T
NM_001425329.1:c.294-2A>T
NM_001425332.1:c.83-2131A>T
NC_000001.10:g.100327811A>T
NM_000028.2:c.294-2A>T
NM_000642.2:c.294-2A>T

Links:

dbSNP: rs1057516868

NCBI 1000 Genomes Browser:

rs1057516868

Molecular consequence:

NM_001425332.1:c.83-2131A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000028.2:c.294-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_000028.3:c.294-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_000642.3:c.294-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_000643.3:c.294-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_000644.3:c.294-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_000646.3:c.246-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001425325.1:c.294-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001425326.1:c.294-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001425327.1:c.294-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001425328.1:c.294-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001425329.1:c.294-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Glycogen storage disease type III (GSD3)
Synonyms:: Glycogen storage disease type 3; Forbes disease; Cori disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009291; MedGen: C0017922; Orphanet: 366; OMIM: 232400

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Mus musculus zinc finger, CCHC domain containing 10 (Zcchc10), mRNA
Mus musculus zinc finger, CCHC domain containing 10 (Zcchc10), mRNA
gi|146135040|ref|NM_026479.4|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001575137	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 11, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 19299494, 31130284, 28492532
SCV002022997	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 27, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002060306	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Nov 19, 2021)	unknown	clinical testing	Citation Link,
SCV002091435	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Feb 3, 2020)	germline	clinical testing
SCV002784004	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 25, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004049916	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004215291	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004804867	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 17, 2024)	germline	research	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Distinct mutations in the glycogen debranching enzyme found in glycogen storage disease type III lead to impairment in diverse cellular functions.

Cheng A, Zhang M, Okubo M, Omichi K, Saltiel AR.

Hum Mol Genet. 2009 Jun 1;18(11):2045-52. doi: 10.1093/hmg/ddp128. Epub 2009 Mar 19.

PubMed [citation]

PMID:: 19299494
PMCID:: PMC2678930

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001575137.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change affects an acceptor splice site in intron 3 of the AGL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of AGL-related conditions (PMID: 31130284). ClinVar contains an entry for this variant (Variation ID: 370920). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002022997.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV002060306.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

NM_000642.2(AGL):c.294-2A>T is a canonical splice variant classified as likely pathogenic in the context of glycogen storage disease type III. c.294-2A>T has not been observed in cases with relevant disease. Functional assessments of this variant are not available in the literature. c.294-2A>T has not been observed in population frequency databases. In summary, NM_000642.2(AGL):c.294-2A>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease and is predicted to disrupt protein function. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002091435.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002784004.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV004049916.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004215291.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004804867.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

Relating variation to medicine