NM_000642.3(AGL):c.753_756del (p.Asp251fs) AND Glycogen storage disease type III

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Mar 26, 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:: RCV000409582.27

Allele description [Variation Report for NM_000642.3(AGL):c.753_756del (p.Asp251fs)]

NM_000642.3(AGL):c.753_756del (p.Asp251fs)

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.753_756del (p.Asp251fs)

HGVS:

NC_000001.11:g.99870488_99870491del
NG_012865.1:g.25405_25408del
NM_000028.3:c.753_756delCAGA
NM_000642.3:c.753_756delMANE SELECT
NM_000643.3:c.753_756delCAGA
NM_000644.3:c.753_756delCAGA
NM_000646.3:c.705_708delCAGA
NM_001425325.1:c.753_756delCAGA
NM_001425326.1:c.753_756delCAGA
NM_001425327.1:c.753_756delCAGA
NM_001425328.1:c.549_552delCAGA
NM_001425329.1:c.549_552delCAGA
NM_001425332.1:c.375_378delCAGA
NP_000019.2:p.Asp251Glufs
NP_000019.2:p.Asp251fs
NP_000633.2:p.Asp251fs
NP_000634.2:p.Asp251Glufs
NP_000634.2:p.Asp251fs
NP_000635.2:p.Asp251Glufs
NP_000635.2:p.Asp251fs
NP_000637.2:p.Asp235Glufs
NP_000637.2:p.Asp235fs
NP_001412254.1:p.Asp251Glufs
NP_001412255.1:p.Asp251Glufs
NP_001412256.1:p.Asp251Glufs
NP_001412257.1:p.Asp183Glufs
NP_001412258.1:p.Asp183Glufs
NP_001412261.1:p.Asp125Glufs
NC_000001.10:g.100336041_100336044del
NC_000001.10:g.100336044_100336047del
NM_000028.2:c.753_756del
NM_000642.2:c.753_756del
NM_000642.2:c.753_756delCAGA
NM_000642.3:c.750_753delAGACMANE SELECT
NM_000642.3:c.753_756del
NM_000643.2:c.753_756del
NM_000644.2:c.753_756del
NM_000646.2:c.705_708del

Protein change:

D235fs

Links:

dbSNP: rs748789700

NCBI 1000 Genomes Browser:

rs748789700

Molecular consequence:

NM_000028.3:c.753_756delCAGA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000642.3:c.753_756del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000643.3:c.753_756delCAGA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000644.3:c.753_756delCAGA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000646.3:c.705_708delCAGA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425325.1:c.753_756delCAGA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425326.1:c.753_756delCAGA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425327.1:c.753_756delCAGA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425328.1:c.549_552delCAGA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425329.1:c.549_552delCAGA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425332.1:c.375_378delCAGA - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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

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nuclear distribution protein nudE-like 1 [Rattus norvegicus]
nuclear distribution protein nudE-like 1 [Rattus norvegicus]
gi|18959268|ref|NP_579854.1|

Protein
MED14P1 mediator complex subunit 14 pseudogene 1 [Homo sapiens]
MED14P1 mediator complex subunit 14 pseudogene 1 [Homo sapiens]
Gene ID:359791

Gene
MED14P1 AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000485852	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Feb 26, 2016)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25431232, 16705713, 23430490, 16189622 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000626766	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19299494, 16189622, 16705713, 23430490, 25431232, 28492532
SCV000918404	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 9, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23430490, 16189622, 25451272, 21321962 Citation Link,
SCV001424356	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001976629	Centre for Human Genetics	no assertion criteria provided	Pathogenic (Aug 10, 2021)	inherited	clinical testing
SCV002023008	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002055471	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]
SCV002091454	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 12, 2020)	germline	clinical testing
SCV002318736	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16189622, 25741868
SCV002812641	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 5, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004211179	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 26, 2024)	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	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	1	1	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

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

Hepatic and neuromuscular forms of glycogenosis type III: nine mutations in AGL.

Lucchiari S, Pagliarani S, Salani S, Filocamo M, Di Rocco M, Melis D, Rodolico C, Musumeci O, Toscano A, Bresolin N, Comi GP.

Hum Mutat. 2006 Jun;27(6):600-1.

PubMed [citation]

PMID:: 16705713

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000485852.2

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000626766.8

#	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.Asp251Glufs*23) 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 (rs748789700, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with glycogen storage disease type III with or without cardiomyopathy (PMID: 16189622, 16705713, 23430490, 25431232). ClinVar contains an entry for this variant (Variation ID: 370509). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918404.1

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

Description

Variant summary: AGL c.753_756delCAGA (p.Asp251GlufsX23) 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. c.2039G>A, p.Trp680X; c.2929C>T, p.Arg977X, c.3216_3217delGA, p.Glu1072fsX36). The variant allele was found at a frequency of 2.9e-05 in 277370 control chromosomes (gnomAD and publications). The variant, c.753_756delCAGA, has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type III in both homozygous and compound heterozygous form (Sentner_2012, Okubo_2011, Endo_2005, Li_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Sentner_2012, Li_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified 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 Centogene AG - the Rare Disease Company, SCV001424356.1

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

From Centre for Human Genetics, SCV001976629.1

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

Description

disease causing

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

From Revvity Omics, Revvity, SCV002023008.3

#	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, SCV002055471.1

#	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., SCV002091454.1

#	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 3billion, SCV002318736.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000370509, PMID:16189622). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000357). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Fulgent Genetics, Fulgent Genetics, SCV002812641.1

#	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 Baylor Genetics, SCV004211179.2

#	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

Last Updated: Sep 29, 2024

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