NM_000642.3(AGL):c.1384del (p.Trp461_Val462insTer) AND Glycogen storage disease type III

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 22, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000169486.8

Allele description [Variation Report for NM_000642.3(AGL):c.1384del (p.Trp461_Val462insTer)]

NM_000642.3(AGL):c.1384del (p.Trp461_Val462insTer)

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.1384del (p.Trp461_Val462insTer)
HGVS:
  • NC_000001.11:g.99876558del
  • NG_012865.1:g.31475del
  • NM_000028.2:c.1384del
  • NM_000642.3:c.1384delMANE SELECT
  • NM_000643.2:c.1384del
  • NM_000644.2:c.1384del
  • NM_000646.2:c.1336del
  • NP_000019.2:p.Trp461_Val462insTer
  • NP_000633.2:p.Trp461_Val462insTer
  • NP_000634.2:p.Trp461_Val462insTer
  • NP_000635.2:p.Trp461_Val462insTer
  • NP_000637.2:p.Trp445_Val446insTer
  • NC_000001.10:g.100342112del
  • NC_000001.10:g.100342114del
  • NM_000642.2:c.1384del
  • NM_000642.2:c.1384delG
  • NM_000642.3:c.1384delGMANE SELECT
Links:
dbSNP: rs786204678
NCBI 1000 Genomes Browser:
rs786204678
Molecular consequence:
  • NM_000028.2:c.1384del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000642.3:c.1384del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000643.2:c.1384del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000644.2:c.1384del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000646.2:c.1336del - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000220939Counsylcriteria provided, single submitter
Likely pathogenic
(Dec 9, 2014)
unknownliterature only

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

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000818823Invitaecriteria provided, single submitter
Pathogenic
(Oct 22, 2020)
germlineclinical testing

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

SCV000916429Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Nov 30, 2018)
germlineclinical testing

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

Citation Link,

SCV001454507Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot 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 (3)

Details of each submission

From Counsyl, SCV000220939.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000818823.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Val462*) in the AGL gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed as homozygous in several individuals affected with glycogen storage disease, type III (GSD III) (PMID: 20648714). ClinVar contains an entry for this variant (Variation ID: 189080). 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, SCV000916429.1

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

Description

Variant summary: AGL c.1384delG (p.Val462X) 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 (eg. p.Trp680X, p.Arg864X, p.Arg977X). The variant allele was found at a frequency of 4.1e-06 in 245906 control chromosomes (gnomAD). c.1384delG has been reported in the literature in homozygous individuals affected with Glycogen Storage Disease Type III (Golstein_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites 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

From Natera, Inc., SCV001454507.1

#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: Jun 14, 2021

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