NM_000642.3(AGL):c.2681+1G>A AND Glycogen storage disease type III

Clinical significance:Pathogenic (Last evaluated: Sep 21, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000377764.9

Allele description [Variation Report for NM_000642.3(AGL):c.2681+1G>A]

NM_000642.3(AGL):c.2681+1G>A

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.2681+1G>A
HGVS:
  • NC_000001.11:g.99884704G>A
  • NG_012865.1:g.39621G>A
  • NM_000028.2:c.2681+1G>A
  • NM_000642.3:c.2681+1G>AMANE SELECT
  • NM_000643.2:c.2681+1G>A
  • NM_000644.2:c.2681+1G>A
  • NM_000646.2:c.2633+1G>A
  • NC_000001.10:g.100350260G>A
  • NM_000642.2:c.2681+1G>A
Links:
dbSNP: rs201201443
NCBI 1000 Genomes Browser:
rs201201443
Molecular consequence:
  • NM_000028.2:c.2681+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_000642.3:c.2681+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_000643.2:c.2681+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_000644.2:c.2681+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_000646.2:c.2633+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000626705Invitaecriteria provided, single submitter
Pathogenic
(Sep 21, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001132327Counsylno assertion criteria providedPathogenic
(Jan 2, 2014)
unknownclinical testing

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

SCV001338430Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Apr 24, 2020)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933

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 (6)

Details of each submission

From Invitae, SCV000626705.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change affects a donor splice site in intron 20 of the AGL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs201201443, ExAC 0.006%). This variant has been observed in several individuals affected with glycogen storage disease (PMID: 10472540, 16705713). ClinVar contains an entry for this variant (Variation ID: 281229). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 10472540). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and 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 Counsyl, SCV001132327.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338430.1

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

Description

Variant summary: AGL c.2681+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in exon 21 skipping (Hadjigeorgiou_AGL_JIMD_1999). The variant allele was found at a frequency of 3.2e-05 in 251020 control chromosomes (gnomAD). c.2681+1G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type III (Hadjigeorgiou_1999, Lucchiari_2007). These data indicate that the variant is very likely to be associated with disease. AGL activity and protein were found to be almost absent in patients muscle specimens (Hadjigeorgiou_1999). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Nov 27, 2021

Support Center