NM_000642.3(AGL):c.4422del (p.Ala1475fs) AND Glycogen storage disease type III

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Aug 29, 2023
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:: RCV001193899.9

Allele description [Variation Report for NM_000642.3(AGL):c.4422del (p.Ala1475fs)]

NM_000642.3(AGL):c.4422del (p.Ala1475fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

1p21.2

Genomic location:

Preferred name:

NM_000642.3(AGL):c.4422del (p.Ala1475fs)

HGVS:

NC_000001.11:g.99916672del
NG_012865.1:g.71589del
NM_000028.3:c.4422delT
NM_000642.3:c.4422delMANE SELECT
NM_000643.3:c.4422delT
NM_000644.3:c.4422delT
NM_000646.3:c.4374delT
NM_001425325.1:c.4422delT
NM_001425326.1:c.4401delT
NM_001425327.1:c.4221delT
NM_001425328.1:c.4218delT
NM_001425329.1:c.4083delT
NM_001425332.1:c.4044delT
NP_000019.2:p.Ala1475Glnfs
NP_000019.2:p.Ala1475fs
NP_000633.2:p.Ala1475fs
NP_000634.2:p.Ala1475Glnfs
NP_000634.2:p.Ala1475fs
NP_000635.2:p.Ala1475Glnfs
NP_000635.2:p.Ala1475fs
NP_000637.2:p.Ala1459Glnfs
NP_000637.2:p.Ala1459fs
NP_001412254.1:p.Ala1475Glnfs
NP_001412255.1:p.Ala1468Glnfs
NP_001412256.1:p.Ala1408Glnfs
NP_001412257.1:p.Ala1407Glnfs
NP_001412258.1:p.Ala1362Glnfs
NP_001412261.1:p.Ala1349Glnfs
NC_000001.10:g.100382228del
NM_000028.2:c.4422del
NM_000642.2:c.4422del
NM_000643.2:c.4422del
NM_000644.2:c.4422del
NM_000646.2:c.4374del

Protein change:

A1459fs

Links:

dbSNP: rs1286364615

NCBI 1000 Genomes Browser:

rs1286364615

Molecular consequence:

NM_000028.3:c.4422delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000642.3:c.4422del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000643.3:c.4422delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000644.3:c.4422delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000646.3:c.4374delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425325.1:c.4422delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425326.1:c.4401delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425327.1:c.4221delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425328.1:c.4218delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425329.1:c.4083delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425332.1:c.4044delT - frameshift variant - [Sequence Ontology: SO:0001589]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001363065	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Sep 16, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001392685	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 29, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20648714, 19299494, 28492532
SCV002055512	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004190950	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 28, 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

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

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 (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363065.1

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

Description

Variant summary: AGL c.4422delT (p.Ala1475GlnfsX4) 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. A truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250766 control chromosomes (gnomAD). c.4422delT has been reported in the literature in an individual affected with Glycogen Storage Disease Type III (Goldstein_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001392685.4

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 929046). This premature translational stop signal has been observed in individual(s) with clinical features of glycogen storage disease type III (PMID: 20648714). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Ala1475Glnfs*4) 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).

#	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, SCV002055512.1

#	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, SCV004190950.1

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine