NM_000642.3(AGL):c.4459C>T (p.Arg1487Ter) AND Glycogen storage disease type III

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jan 7, 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:: RCV000531434.20

Allele description [Variation Report for NM_000642.3(AGL):c.4459C>T (p.Arg1487Ter)]

NM_000642.3(AGL):c.4459C>T (p.Arg1487Ter)

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.4459C>T (p.Arg1487Ter)

HGVS:

NC_000001.11:g.99916709C>T
NG_012865.1:g.71626C>T
NM_000028.3:c.4459C>T
NM_000642.3:c.4459C>TMANE SELECT
NM_000643.3:c.4459C>T
NM_000644.3:c.4459C>T
NM_000646.3:c.4411C>T
NM_001425325.1:c.4459C>T
NM_001425326.1:c.4438C>T
NM_001425327.1:c.4258C>T
NM_001425328.1:c.4255C>T
NM_001425329.1:c.4120C>T
NM_001425332.1:c.4081C>T
NP_000019.2:p.Arg1487Ter
NP_000019.2:p.Arg1487Ter
NP_000633.2:p.Arg1487Ter
NP_000634.2:p.Arg1487Ter
NP_000634.2:p.Arg1487Ter
NP_000635.2:p.Arg1487Ter
NP_000635.2:p.Arg1487Ter
NP_000637.2:p.Arg1471Ter
NP_000637.2:p.Arg1471Ter
NP_001412254.1:p.Arg1487Ter
NP_001412255.1:p.Arg1480Ter
NP_001412256.1:p.Arg1420Ter
NP_001412257.1:p.Arg1419Ter
NP_001412258.1:p.Arg1374Ter
NP_001412261.1:p.Arg1361Ter
NC_000001.10:g.100382265C>T
NM_000028.2:c.4459C>T
NM_000642.2:c.4459C>T
NM_000642.3:c.4459C>T
NM_000643.2:c.4459C>T
NM_000644.2:c.4459C>T
NM_000646.2:c.4411C>T
p.Arg1487X

Protein change:

R1361*

Links:

dbSNP: rs12118058

NCBI 1000 Genomes Browser:

rs12118058

Molecular consequence:

NM_000028.3:c.4459C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_000642.3:c.4459C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_000643.3:c.4459C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_000644.3:c.4459C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_000646.3:c.4411C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001425325.1:c.4459C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001425326.1:c.4438C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001425327.1:c.4258C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001425328.1:c.4255C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001425329.1:c.4120C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001425332.1:c.4081C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000626760	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 7, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 29374762, 8990006, 20071996, 20490926, 23430490, 28492532
SCV000793936	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Sep 8, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002023703	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 23, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002055551	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002500079	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Mar 4, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17994282, 31980526, 29374762 Citation Link,
SCV004214542	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 3, 2023)	unknown	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	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Bao Y, Chen YT.

Hum Mutat. 1997;9(1):37-40.

PubMed [citation]

PMID:: 8990006

The electrodiagnostic characteristics of Glycogen Storage Disease Type III.

Hobson-Webb LD, Austin SL, Bali DS, Kishnani PS.

Genet Med. 2010 Jul;12(7):440-5. doi: 10.1097/GIM.0b013e3181cd735b.

PubMed [citation]

PMID:: 20071996

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000626760.7

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

Description

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.

#	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, SCV000793936.1

#	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, SCV002023703.3

#	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 Genome-Nilou Lab, SCV002055551.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002500079.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	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, SCV004214542.1

#	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

Last Updated: Mar 16, 2024

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