NM_000642.3(AGL):c.4260-12A>G AND Glycogen storage disease type III

Germline classification:: Pathogenic/Likely pathogenic (11 submissions)
Last evaluated:: Mar 29, 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:: RCV000020379.28

Allele description [Variation Report for NM_000642.3(AGL):c.4260-12A>G]

NM_000642.3(AGL):c.4260-12A>G

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.4260-12A>G

HGVS:

NC_000001.11:g.99916398A>G
NG_012865.1:g.71315A>G
NM_000028.2:c.4260-12A>G
NM_000642.3:c.4260-12A>GMANE SELECT
NM_000643.2:c.4260-12A>G
NM_000644.2:c.4260-12A>G
NM_000646.2:c.4212-12A>G
NC_000001.10:g.100381954A>G
NM_000642.2:c.4260-12A>G

Nucleotide change:

IVS32AS, A-G, -12

Links:

OMIM: 610860.0006; dbSNP: rs369973784

NCBI 1000 Genomes Browser:

rs369973784

Molecular consequence:

NM_000028.2:c.4260-12A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000642.3:c.4260-12A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000643.2:c.4260-12A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000644.2:c.4260-12A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000646.2:c.4212-12A>G - intron variant - [Sequence Ontology: SO:0001627]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000055699	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000220759	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Sep 30, 2014)	unknown	literature only	PubMed (6) [See all records that cite these PMIDs] 10655153, 20648714, 9490286, 22089644, 23430490, 11924557 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000626749	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10655153, 11924557, 20648714, 22089644, 23430490, 25827695, 9490286, 28492532
SCV001162837	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001362038	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 31, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23430490, 26984562, 10655153, 10801050, 9490286 Citation Link,
SCV001623484	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002094577	Natera, Inc.	no assertion criteria provided	Pathogenic (Jul 20, 2020)	germline	clinical testing
SCV002556779	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 12, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002778005	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 7, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004235534	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 21, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004805787	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Mutational and haplotype analysis of AGL in patients with glycogen storage disease type III.

Horinishi A, Okubo M, Tang NL, Hui J, To KF, Mabuchi T, Okada T, Mabuchi H, Murase T.

J Hum Genet. 2002;47(2):55-9.

PubMed [citation]

PMID:: 11924557

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, Austin SL, Boyette K, Kanaly A, Veerapandiyan A, Rehder C, Kishnani PS, Bali DS.

Genet Med. 2010 Jul;12(7):424-30. doi: 10.1097/GIM.0b013e3181d94eaa.

PubMed [citation]

PMID:: 20648714

See all PubMed Citations (11)

Details of each submission

From GeneReviews, SCV000055699.3

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

Description

Associated with milder phenotype

#	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 Counsyl, SCV000220759.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (6)

#	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 Invitae, SCV000626749.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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.

#	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 Baylor Genetics, SCV001162837.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362038.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	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 Genome-Nilou Lab, SCV001623484.1

#	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 Natera, Inc., SCV002094577.1

#	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 Genetics and Molecular Pathology, SA Pathology, SCV002556779.2

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002778005.1

#	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 Revvity Omics, Revvity, SCV004235534.1

#	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	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, SCV004805787.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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