NM_000642.3(AGL):c.4456del (p.Ser1486fs) AND Glycogen storage disease type III

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Sep 26, 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:: RCV000177731.19

Allele description [Variation Report for NM_000642.3(AGL):c.4456del (p.Ser1486fs)]

NM_000642.3(AGL):c.4456del (p.Ser1486fs)

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.4456del (p.Ser1486fs)

HGVS:

NC_000001.11:g.99916706del
NG_012865.1:g.71623del
NM_000028.3:c.4456delT
NM_000642.3:c.4456delMANE SELECT
NM_000643.3:c.4456delT
NM_000644.3:c.4456delT
NM_000646.3:c.4408delT
NM_001425325.1:c.4456delT
NM_001425326.1:c.4435delT
NM_001425327.1:c.4255delT
NM_001425328.1:c.4252delT
NM_001425329.1:c.4117delT
NM_001425332.1:c.4078delT
NP_000019.2:p.Ser1486Profs
NP_000019.2:p.Ser1486fs
NP_000633.2:p.Ser1486fs
NP_000634.2:p.Ser1486Profs
NP_000634.2:p.Ser1486fs
NP_000635.2:p.Ser1486Profs
NP_000635.2:p.Ser1486fs
NP_000637.2:p.Ser1470Profs
NP_000637.2:p.Ser1470fs
NP_001412254.1:p.Ser1486Profs
NP_001412255.1:p.Ser1479Profs
NP_001412256.1:p.Ser1419Profs
NP_001412257.1:p.Ser1418Profs
NP_001412258.1:p.Ser1373Profs
NP_001412261.1:p.Ser1360Profs
NC_000001.10:g.100382260del
NC_000001.10:g.100382262del
NM_000028.2:c.4456del
NM_000642.2:c.4455delT
NM_000642.2:c.4456del
NM_000642.2:c.4456delT
NM_000642.3:c.4456delTMANE SELECT
NM_000643.2:c.4456del
NM_000644.2:c.4456del
NM_000646.2:c.4408del

Protein change:

S1470fs

Links:

OMIM: 610860.0005; dbSNP: rs113994134

NCBI 1000 Genomes Browser:

rs113994134

Molecular consequence:

NM_000028.3:c.4456delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000642.3:c.4456del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000643.3:c.4456delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000644.3:c.4456delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000646.3:c.4408delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425325.1:c.4456delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425326.1:c.4435delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425327.1:c.4255delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425328.1:c.4252delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425329.1:c.4117delT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001425332.1:c.4078delT - 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
SCV000040768	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9412782, 25602008
SCV000626759	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 26, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9412782, 25388549, 25602008, 27065010, 27460348, 28492532
SCV001194233	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 20, 2019)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9412782, 25602008 Citation Link,
SCV001460667	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002055513	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]
SCV002573158	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25388549, 9412782, 25741868
SCV004215224	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 20, 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	unknown	unknown	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, literature only

Citations

PubMed

Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases.

Chen R, Shi L, Hakenberg J, Naughton B, Sklar P, Zhang J, Zhou H, Tian L, Prakash O, Lemire M, Sleiman P, Cheng WY, Chen W, Shah H, Shen Y, Fromer M, Omberg L, Deardorff MA, Zackai E, Bobe JR, Levin E, Hudson TJ, et al.

Nat Biotechnol. 2016 May;34(5):531-8. doi: 10.1038/nbt.3514. Epub 2016 Apr 11.

PubMed [citation]

PMID:: 27065010

Cross-sectional retrospective study of muscle function in patients with glycogen storage disease type III.

Decostre V, Laforêt P, Nadaj-Pakleza A, De Antonio M, Leveugle S, Ollivier G, Canal A, Kachetel K, Petit F, Eymard B, Behin A, Wahbi K, Labrune P, Hogrel JY.

Neuromuscul Disord. 2016 Sep;26(9):584-92. doi: 10.1016/j.nmd.2016.06.460. Epub 2016 Jun 28.

PubMed [citation]

PMID:: 27460348

See all PubMed Citations (7)

Details of each submission

From GeneReviews, SCV000040768.3

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

Description

Founder variant in North African Jewish persons and those of Inuit descent

#	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, SCV000626759.3

#	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.Ser1486Profs*18) in the AGL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the AGL protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with glycogen storage disease III (PMID: 9412782, 25388549, 25602008, 27065010, 27460348). This variant is also known as c.4455delT. ClinVar contains an entry for this variant (Variation ID: 1098). 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 Myriad Genetics, Inc., SCV001194233.2

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

Description

NM_000642.2(AGL):c.4456delT(S1486Pfs*18) is classified as pathogenic in the context of glycogen storage disease type III. Sources cited for classification include the following: PMID 9412782 and 25602008. Classification of NM_000642.2(AGL):c.4456delT(S1486Pfs*18) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.

#	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., SCV001460667.1

#	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, SCV002055513.1

#	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 3billion, SCV002573158.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 9412782 / 3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25388549 , 9412782 / 3billion dataset). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001098 / PMID: 9412782). 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 Baylor Genetics, SCV004215224.1

#	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: Oct 13, 2024

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