NM_000642.3(AGL):c.3911dup (p.Asn1304fs) AND Glycogen storage disease type III

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

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000412031.11

Allele description [Variation Report for NM_000642.3(AGL):c.3911dup (p.Asn1304fs)]

NM_000642.3(AGL):c.3911dup (p.Asn1304fs)

Gene:
AGL:amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
1p21.2
Genomic location:
Preferred name:
NM_000642.3(AGL):c.3911dup (p.Asn1304fs)
HGVS:
  • NC_000001.11:g.99912479dup
  • NG_012865.1:g.67396dup
  • NM_000028.2:c.3911dup
  • NM_000642.3:c.3903_3904insA
  • NM_000642.3:c.3911dupMANE SELECT
  • NM_000643.2:c.3911dup
  • NM_000644.2:c.3911dup
  • NM_000646.2:c.3863dup
  • NP_000019.2:p.Asn1304fs
  • NP_000633.2:p.Asn1304fs
  • NP_000634.2:p.Asn1304fs
  • NP_000635.2:p.Asn1304fs
  • NP_000637.2:p.Asn1288fs
  • NC_000001.10:g.100378027_100378028insA
  • NC_000001.10:g.100378035dup
  • NM_000642.2:c.3911dup
  • NM_000642.2:c.3911dupA
  • NM_000642.3:c.3903_3904insAMANE SELECT
  • NM_000642.3:c.3911dupAMANE SELECT
  • p.Asn1304Lysfs*7
Protein change:
N1288fs
Links:
dbSNP: rs745757264
NCBI 1000 Genomes Browser:
rs745757264
Molecular consequence:
  • NM_000028.2:c.3911dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_000642.3:c.3911dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_000643.2:c.3911dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_000644.2:c.3911dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_000646.2:c.3863dup - frameshift variant - [Sequence Ontology: SO:0001589]
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
SCV000486246Counsylno assertion criteria providedLikely pathogenic
(Apr 21, 2016)
unknownclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000626744Invitaecriteria provided, single submitter
Pathogenic
(Aug 14, 2020)
germlineclinical testing

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

SCV001363064Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Sep 21, 2020)
germlineclinical testing

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

Citation Link,

SCV001456552Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

SCV001482490Centre for Human Geneticscriteria provided, single submitter
Likely pathogenic
(Aug 27, 2020)
inheritedclinical testing

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

SCV002023692PerkinElmer Genomicsno assertion criteria providedPathogenic
(Dec 7, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedinheritedyes11not providednot providednot providedclinical 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 (7)

Details of each submission

From Counsyl, SCV000486246.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000626744.5

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

Description

This sequence change creates a premature translational stop signal (p.Asn1304Lysfs*7) in the AGL gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported as homozygous and in combination with another AGL variant in individuals affected with glycogen storage disease type III (PMID: 9584265, 23430832 , 23430832, Invitae). This variant is also known as c.3904insA in the literature. ClinVar contains an entry for this variant (Variation ID: 370832). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363064.2

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

Description

Variant summary: AGL c.3911dupA (p.Asn1304LysfsX7) 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. The variant allele was found at a frequency of 4e-05 in 249526 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in AGL causing Glycogen Storage Disease Type III (4e-05 vs 0.0023), allowing no conclusion about variant significance. c.3911dupA (also known as c.3904insA) has been reported in the literature, in the compound heterozygous and homozygous state, in multiple individuals affected with Glycogen Storage Disease Type III (e.g. Parvari_1997, Lee_2011). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated very low enzymatic activity and glycogen accumulation in the liver, in homozygous patients (Lee_2011, Ponzi_2019). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely 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

From Natera, Inc., SCV001456552.1

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

From Centre for Human Genetics, SCV001482490.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

disease causing

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot provided1not provided1not provided

From PerkinElmer Genomics, SCV002023692.1

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

Last Updated: Nov 28, 2021

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