NM_000642.3(AGL):c.2039G>A (p.Trp680Ter) AND Glycogen storage disease type III

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jun 18, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000020375.10

Allele description [Variation Report for NM_000642.3(AGL):c.2039G>A (p.Trp680Ter)]

NM_000642.3(AGL):c.2039G>A (p.Trp680Ter)

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.2039G>A (p.Trp680Ter)
HGVS:
  • NC_000001.11:g.99881329G>A
  • NG_012865.1:g.36246G>A
  • NM_000028.2:c.2039G>A
  • NM_000642.3:c.2039G>AMANE SELECT
  • NM_000643.2:c.2039G>A
  • NM_000644.2:c.2039G>A
  • NM_000646.2:c.1991G>A
  • NP_000019.2:p.Trp680Ter
  • NP_000633.2:p.Trp680Ter
  • NP_000634.2:p.Trp680Ter
  • NP_000635.2:p.Trp680Ter
  • NP_000637.2:p.Trp664Ter
  • NC_000001.10:g.100346885G>A
  • NM_000642.2:c.2039G>A
Protein change:
W664*; TRP680TER
Links:
OMIM: 610860.0003; dbSNP: rs113994129
NCBI 1000 Genomes Browser:
rs113994129
Molecular consequence:
  • NM_000028.2:c.2039G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000642.3:c.2039G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000643.2:c.2039G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000644.2:c.2039G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000646.2:c.1991G>A - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000040763GeneReviewsno assertion criteria providedpathologic
(Sep 6, 2012)
not providedcuration

SCV000918401Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jan 11, 2018)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001224259Invitaecriteria provided, single submitter
Pathogenic
(Jun 18, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001429967Institute of Human Genetics, Klinikum rechts der Isarcriteria provided, single submitter
Pathogenic
(Jun 9, 2020)
germlineclinical testing

Citation Link,

SCV001441057Institute of Human Genetics, University of Leipzig Medical Centercriteria provided, single submitter
Likely pathogenic
(Jan 1, 2019)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot providednot providednot providedcuration
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyes1not providednot provided1not providedclinical testing

Citations

PubMed

Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle.

Shen J, Bao Y, Liu HM, Lee P, Leonard JV, Chen YT.

J Clin Invest. 1996 Jul 15;98(2):352-7.

PubMed [citation]
PMID:
8755644
PMCID:
PMC507437

Mutation Analysis in Glycogen Storage Disease Type III Patients in the Netherlands: Novel Genotype-Phenotype Relationships and Five Novel Mutations in the AGL Gene.

Sentner CP, Vos YJ, Niezen-Koning KN, Mol B, Smit GP.

JIMD Rep. 2013;7:19-26. doi: 10.1007/8904_2012_134. Epub 2012 Mar 16.

PubMed [citation]
PMID:
23430490
PMCID:
PMC3575051
See all PubMed Citations (5)

Details of each submission

From GeneReviews, SCV000040763.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918401.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: The AGL c.2039G>A (p.Trp680X) variant results in a premature termination codon, predicted to cause a truncated or absent AGL 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 (c.2929C>T, p.Arg977X). One in silico tool predicts a damaging outcome for this variant. One functional study showed no GSD residual activity in GSD IIIa patients homozygous for this variant in leukocytes, fibroblasts, and/or liver tissue, and/or muscle tissue (Sentner_2012). This variant was found in 2/245574 control chromosomes in gnomAD at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic AGL variant (0.0022822).This variant has been reported in 4 homozygous patients of Caribbean origin with GSD IIIa (Sentner_2012) and also in one patient diagnosed with GSD type IIIb in compound heterozygosity with AGL c.16C>T (p.Gln6Ter)( Shen_AGL_JCI_1996). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001224259.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Trp680*) in the AGL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs113994129, ExAC 0.003%). This variant has been observed in an individual affected with glycogen storage disease type III (GSDIII) (PMID: 8755644, 23430490). ClinVar contains an entry for this variant (Variation ID: 1096). Loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Institute of Human Genetics, Klinikum rechts der Isar, SCV001429967.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1bloodnot provided1not providednot providednot provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001441057.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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