NM_000642.3(AGL):c.3216_3217del (p.Glu1072fs) AND Glycogen storage disease type III

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jan 28, 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:: RCV000596959.16

Allele description [Variation Report for NM_000642.3(AGL):c.3216_3217del (p.Glu1072fs)]

NM_000642.3(AGL):c.3216_3217del (p.Glu1072fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

1p21.2

Genomic location:

Preferred name:

NM_000642.3(AGL):c.3216_3217del (p.Glu1072fs)

HGVS:

NC_000001.11:g.99892562GA[1]
NG_012865.1:g.47479GA[1]
NM_000028.3:c.3214_3215GA[1]
NM_000642.3:c.3216_3217delMANE SELECT
NM_000643.3:c.3214_3215GA[1]
NM_000644.3:c.3214_3215GA[1]
NM_000646.3:c.3166_3167GA[1]
NM_001425325.1:c.3214_3215GA[1]
NM_001425326.1:c.3193_3194GA[1]
NM_001425327.1:c.3013_3014GA[1]
NM_001425328.1:c.3010_3011GA[1]
NM_001425329.1:c.2875_2876GA[1]
NM_001425332.1:c.2836_2837GA[1]
NP_000019.2:p.Glu1072Aspfs
NP_000019.2:p.Glu1072fs
NP_000633.2:p.Glu1072fs
NP_000634.2:p.Glu1072Aspfs
NP_000634.2:p.Glu1072fs
NP_000635.2:p.Glu1072Aspfs
NP_000635.2:p.Glu1072fs
NP_000637.2:p.Glu1056Aspfs
NP_000637.2:p.Glu1056fs
NP_001412254.1:p.Glu1072Aspfs
NP_001412255.1:p.Glu1065Aspfs
NP_001412256.1:p.Glu1005Aspfs
NP_001412257.1:p.Glu1004Aspfs
NP_001412258.1:p.Glu959Aspfs
NP_001412261.1:p.Glu946Aspfs
NC_000001.10:g.100358118GA[1]
NC_000001.10:g.100358118_100358119del
NM_000028.2:c.3216_3217del
NM_000028.2:c.3216_3217del
NM_000642.2:c.3216_3217delGA
NM_000642.3:c.3216_3217delGAMANE SELECT
NM_000643.2:c.3216_3217del
NM_000644.2:c.3216_3217del
NM_000646.2:c.3168_3169del

Protein change:

E1056fs

Links:

dbSNP: rs771069887

NCBI 1000 Genomes Browser:

rs771069887

Molecular consequence:

NM_000028.3:c.3214_3215GA[1] - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000642.3:c.3216_3217del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000643.3:c.3214_3215GA[1] - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000644.3:c.3214_3215GA[1] - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000646.3:c.3166_3167GA[1] - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425325.1:c.3214_3215GA[1] - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425326.1:c.3193_3194GA[1] - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425327.1:c.3013_3014GA[1] - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425328.1:c.3010_3011GA[1] - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425329.1:c.2875_2876GA[1] - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425332.1:c.2836_2837GA[1] - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000834601	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19299494, 20648714, 22035446, 28888851, 28492532
SCV001132329	Counsyl	no assertion criteria provided	Likely pathogenic (Jul 11, 2015)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20648714, 22035446
SCV001456540	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002055494	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]
SCV002061252	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20648714, 22035446, 28888851, 25741868
SCV002799151	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 8, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004216816	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 19, 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	yes	1	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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000834601.7

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

Description

This sequence change creates a premature translational stop signal (p.Glu1072Aspfs*36) 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 (rs771069887, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with glycogen storage disease type III (PMID: 20648714, 22035446, 28888851). ClinVar contains an entry for this variant (Variation ID: 432008). 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, SCV001132329.1

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

#	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., SCV001456540.1

#	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 Genome-Nilou Lab, SCV002055494.1

#	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 DASA, SCV002061252.1

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

Description

The c.3216_3217del;p.(Glu1072Aspfs*36) is a null frameshift variant (NMD) in the AGL gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 432008; PMID: 20648714; 22035446; 28888851) - PS4. The variant is present at low allele frequencies population databases (rs771069887– gnomAD 0.003286%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Glu1072Aspfs*36) was detected in trans with a pathogenic variant (PMID: 28888851) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.

#	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		1	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002799151.1

#	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, SCV004216816.1

#	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 5, 2024

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