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NM_000158.4(GBE1):c.986A>G (p.Tyr329Cys) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 29, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000529291.9

Allele description [Variation Report for NM_000158.4(GBE1):c.986A>G (p.Tyr329Cys)]

NM_000158.4(GBE1):c.986A>G (p.Tyr329Cys)

Gene:
GBE1:1,4-alpha-glucan branching enzyme 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p12.2
Genomic location:
Preferred name:
NM_000158.4(GBE1):c.986A>G (p.Tyr329Cys)
Other names:
NM_000158.4(GBE1):c.986A>G; p.Tyr329Cys
HGVS:
  • NC_000003.12:g.81642787T>C
  • NG_011810.1:g.124014A>G
  • NM_000158.4:c.986A>GMANE SELECT
  • NP_000149.4:p.Tyr329Cys
  • NC_000003.11:g.81691938T>C
  • NM_000158.3:c.986A>G
Protein change:
Y329C
Links:
dbSNP: rs80338671
NCBI 1000 Genomes Browser:
rs80338671
Molecular consequence:
  • NM_000158.4:c.986A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Glycogen storage disease, type IV (GSD4)
Synonyms:
GBE1 DEFICIENCY; GLYCOGENOSIS IV; GSD IV; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009292; MedGen: C0017923; Orphanet: 367; OMIM: 232500
Name:
Glycogen storage disease IV, classic hepatic
Synonyms:
GSD IV, CLASSIC HEPATIC
Identifiers:
MedGen: C1856301

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000626777Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Jan 29, 2024)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Adult polyglucosan body disease: Natural History and Key Magnetic Resonance Imaging Findings.

Mochel F, Schiffmann R, Steenweg ME, Akman HO, Wallace M, Sedel F, LaforĂȘt P, Levy R, Powers JM, Demeret S, Maisonobe T, Froissart R, Da Nobrega BB, Fogel BL, Natowicz MR, Lubetzki C, Durr A, Brice A, Rosenmann H, Barash V, Kakhlon O, Gomori JM, et al.

Ann Neurol. 2012 Sep;72(3):433-41. doi: 10.1002/ana.23598.

PubMed [citation]
PMID:
23034915
PMCID:
PMC4329926

Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene.

Bao Y, Kishnani P, Wu JY, Chen YT.

J Clin Invest. 1996 Feb 15;97(4):941-8.

PubMed [citation]
PMID:
8613547
PMCID:
PMC507139
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000626777.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 329 of the GBE1 protein (p.Tyr329Cys). This variant is present in population databases (rs80338671, gnomAD 0.08%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with adult polyglucosan body disease (PMID: 23034915). ClinVar contains an entry for this variant (Variation ID: 371439). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GBE1 protein function with a positive predictive value of 95%. This variant disrupts the p.Tyr329 amino acid residue in GBE1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8613547, 25665141, 26199317, 26385640). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Jul 15, 2024