ClinVar Genomic variation as it relates to human health
NM_000158.4(GBE1):c.986A>C (p.Tyr329Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000158.4(GBE1):c.986A>C (p.Tyr329Ser)
Variation ID: 2777 Accession: VCV000002777.55
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p12.2 3: 81642787 (GRCh38) [ NCBI UCSC ] 3: 81691938 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Apr 15, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000158.4:c.986A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000149.4:p.Tyr329Ser missense NC_000003.12:g.81642787T>G NC_000003.11:g.81691938T>G NG_011810.1:g.124014A>C Q04446:p.Tyr329Ser - Protein change
- Y329S
- Other names
- NM_000158.4(GBE1):c.986A>C
- Canonical SPDI
- NC_000003.12:81642786:T:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00018
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GBE1 | - | - |
GRCh38 GRCh37 |
980 | 996 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Dec 1, 1998 | RCV000002907.11 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 28, 2023 | RCV000020163.9 | |
Pathogenic (1) |
no assertion criteria provided
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Dec 1, 1998 | RCV000150105.10 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jun 3, 2022 | RCV000493505.30 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 7, 2018 | RCV000304728.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 29, 2022 | RCV000763520.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2024 | RCV000555363.9 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2022 | RCV000991160.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Sep 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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GBE1-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000446301.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The GBE1 c.986A>C (p.Tyr329Ser) missense variant has been reported in at least six studies in which it is found in a total of 82 individuals … (more)
The GBE1 c.986A>C (p.Tyr329Ser) missense variant has been reported in at least six studies in which it is found in a total of 82 individuals with glycogen storage disease type IV or adult polyglucosan body disease, including in 48 in a homozygous state, in 25 in a compound heterozygous state, and in nine in a heterozygous state where a second variant was not detected (Bao et al. 1996; Lossos et al. 1998; Roe et al. 2010; DiMauro and Spiegel 2011; Mochel et al. 2013; Akman et al. 2015). The p.Tyr329Ser variant was absent from 143 controls but is reported at a frequency of 0.00045 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated that the expression of recombinant protein carrying the p.Tyr329Ser variant resulted in a drastically reduced protein yield and solubility, suggesting that the variant leads to protein misfolding (Froese et al. 2015). The variant has also been shown to result in decreased enzyme activity ranging from undetectable levels to 50% of wild type (Bao et al. 1996; Lossos et al. 1998; Mochel et al. 2013; Akman et al. 2015). Based on the collective evidence, the p.Tyr329Ser variant is classified as pathogenic for GBE1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Dec 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type IV
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001193775.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
NM_000158.3(GBE1):c.986A>C(Y329S) is classified as pathogenic in the context of GBE1-related disorders and may be associated with adult polyglucosan body disease. Sources cited for classification include … (more)
NM_000158.3(GBE1):c.986A>C(Y329S) is classified as pathogenic in the context of GBE1-related disorders and may be associated with adult polyglucosan body disease. Sources cited for classification include the following: 25665141, 8613547, 26385640, 26199317 and 23607684. Classification of NM_000158.3(GBE1):c.986A>C(Y329S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Sep 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000801198.2
First in ClinVar: Jul 02, 2017 Last updated: Jun 08, 2021 |
Comment:
PS3, PS4_moderate, PM2, PM3, PP1, PP3, PP4, PP5
Number of individuals with the variant: 1
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Pathogenic
(Mar 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type IV
Adult polyglucosan body disease
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894327.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000582785.7
First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that the variant is associated with 50% of GBE activity when compared to wild type (Bao et al., 1996); In silico … (more)
Published functional studies demonstrate that the variant is associated with 50% of GBE activity when compared to wild type (Bao et al., 1996); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Common pathogenic variant in the Ashkenazi Jewish population (Akman et al., 2015); This variant is associated with the following publications: (PMID: 24082139, 30185673, 20655781, 26385640, 30228975, 25133958, 31692161, 34103343, 31980526, 31589614, 9851430, 32746448, 33332610, 25665141, 8613547) (less)
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Pathogenic
(Jan 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024211.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type IV
Glycogen storage disease IV, classic hepatic
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000626776.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 329 of the GBE1 protein (p.Tyr329Ser). … (more)
This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 329 of the GBE1 protein (p.Tyr329Ser). This variant is present in population databases (rs80338671, gnomAD 0.6%). This missense change has been observed in individual(s) with adult polyglucosan body disease (PMID: 8613547, 20655781, 24082139, 25133958, 25665141). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8613547, 20655781, 24082139, 25133958, 25665141). ClinVar contains an entry for this variant (Variation ID: 2777). 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%. Experimental studies have shown that this missense change affects GBE1 function (PMID: 8613547, 26199317, 26385640). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248811.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jan 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000700628.2
First in ClinVar: Jul 02, 2017 Last updated: Jul 02, 2017 |
Number of individuals with the variant: 5
Sex: mixed
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Pathogenic
(Apr 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Adult polyglucosan body disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV001245583.2 First in ClinVar: May 12, 2020 Last updated: Jun 19, 2021 |
Observation 1:
Clinical Features:
Neurogenic bladder (present) , Urinary incontinence (present) , Optic atrophy (present) , Nyctalopia (present) , Cerebellar atrophy (present) , Bicuspid aortic valve (present) , Gait … (more)
Neurogenic bladder (present) , Urinary incontinence (present) , Optic atrophy (present) , Nyctalopia (present) , Cerebellar atrophy (present) , Bicuspid aortic valve (present) , Gait ataxia (present) , Broad-based gait (present) , Impaired vibration sensation in the lower limbs (present) , Clumsiness (present) , Leukodystrophy (present) , Hyporeflexia of lower limbs (present) , Bowel incontinence (present) , Pelvic girdle muscle weakness (present) , Increased muscle fatiguability (present) , Delayed brainstem auditory evoked response conduction time (present) , Motor axonal neuropathy (present) , Sensorimotor neuropathy (present) , Atrophy/Degeneration affecting the brainstem (present) , Cervical spinal cord atrophy (present) , Abnormality of central motor conduction (present) , Chronic constipation (present) , Anti-multiple nuclear dots antibody positivity (present) , Preretinal fibrosis (present) (less)
Age: 60-69 years
Sex: female
Ethnicity/Population group: Caucasians
Tissue: blood
Observation 2:
Clinical Features:
Hyporeflexia (present) , Tremor (present) , Hepatic steatosis (present) , Asthma (present) , Gait imbalance (present) , Unsteady gait (present) , Action tremor (present) , … (more)
Hyporeflexia (present) , Tremor (present) , Hepatic steatosis (present) , Asthma (present) , Gait imbalance (present) , Unsteady gait (present) , Action tremor (present) , Type II diabetes mellitus (present) , Brain atrophy (present) , Abnormal brainstem MRI signal intensity (present) , Cognitive impairment (present) (less)
Age: 50-59 years
Sex: male
Ethnicity/Population group: Causasians
Tissue: blood
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Pathogenic
(Aug 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type IV
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001821397.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Variant summary: GBE1 c.986A>C (p.Tyr329Ser) results in a non-conservative amino acid change located in the Glycosyl hydrolase, family 13, catalytic domain (IPR006047) of the encoded … (more)
Variant summary: GBE1 c.986A>C (p.Tyr329Ser) results in a non-conservative amino acid change located in the Glycosyl hydrolase, family 13, catalytic domain (IPR006047) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 248464 control chromosomes (gnomAD). c.986A>C has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Adult Polyglucosan Body Disease (APBD) and Glycogen Storage Disease, Type IV (e.g. Bao_1996, Roe_2010, Mochel_2012). APBD occurs most frequently in patients of Ashkenazi Jewish origin due to partial deficiency of the glycogen brancher enzyme, which is most commonly caused by the p.Tyr329Ser mutation (Roe_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant results in protein destabilization and in reduced enzyme activity compared to wild-type (Bao_1996, Akman_2015, Froese_2015). Eleven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 27, 2022)
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criteria provided, single submitter
Method: curation
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Adult polyglucosan body disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV002097106.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment:
The p.Tyr329Ser variant in GBE1 has been reported in many individuals with GBE1-related disorders (PMID: 8613547, 9851430, 20655781, 23034915, 25133958, 25665141, 33332610), segregated with disease … (more)
The p.Tyr329Ser variant in GBE1 has been reported in many individuals with GBE1-related disorders (PMID: 8613547, 9851430, 20655781, 23034915, 25133958, 25665141, 33332610), segregated with disease in 4 affected relatives from 3 families (PMID: 9851430, 20655781, 33332610), and has been identified in 0.6% (65/10038) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs80338671). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 2777) and has been interpreted as pathogenic by multiple submitters in ClinVar. Of the many affected individuals, at least 2 of those were homozygotes, which increases the likelihood that the p.Tyr329Ser variant is pathogenic (PMID: 8613547, 9851430, 20655781, 23034915, 25133958, 25665141, 33332610). Animal models in mice have shown that this variant causes GBE1-related disorders (PMID: 26385640). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive GBE1-related disorder. ACMG/AMP Criteria applied: PP3, PM3, PP1_strong, PS3 (Richards 2015). (less)
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Pathogenic
(Jul 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Adult polyglucosan body disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center
Accession: SCV004190169.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
The variant in the GBE1 gene, c.986A>C is a missense variant, resulting in a tyrosine to serine protein substitution at position 329 (p.Tyr329Ser). This variant … (more)
The variant in the GBE1 gene, c.986A>C is a missense variant, resulting in a tyrosine to serine protein substitution at position 329 (p.Tyr329Ser). This variant localizes to coding exon 7 of the GBE1 gene (16 exons in total; NM_000158.4) and is predicted to damage protein structure and/or function based on in silico analyses (Provean and SIFT). Functional studies show the expression of the recombinant protein carrying the p.Tyr329Ser variant results in drastically reduced protein yield and solubility, suggesting that the variant leads to protein misfolding (PMID: 26199317). The variant has also been shown to result in decreased enzyme activity ranging from undetectable levels to 50% of wild type (PMID: 8613547). This variant has been reported in several studies in either a homozygous or compound heterozygous state with a second known pathogenic variant in unrelated individuals with glycogen storage disease type IV or adult polyglucosan body disease (PMID: 9851430; 20655781; 22106711; 23034915; 25665141; 28265589; 32455116). It is also the most common variant associated with adult polyglucosan body disease in the Ashkenazi Jewish population (PMID: 25665141). This variant is reported in the Genome Aggregation Database (gnomAD) with an allele frequency of 79/248464 (no homozygote), indicating it is not a common benign variant in the populations represented in this database. It has already been interpreted as pathogenic by multiple laboratories in the ClinVar database (variation ID: 2777). (less)
Clinical Features:
Progressive peripheral neuropathy (present) , Urinary incontinence (present) , Gait imbalance (present) , Memory impairment (present) , Spasticity (present)
Family history: yes
Age: 60-69 years
Sex: male
Ethnicity/Population group: Ashkenazi Jew
Comment on evidence:
Observed in trans with c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT
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Pathogenic
(Oct 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type IV
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004198658.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Polyglucosan body disease, adult
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142329.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Comment:
NM_000158.3:c.986A>C in the GBE1 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.986A>C (p.Tyr329Ser) missense variant has … (more)
NM_000158.3:c.986A>C in the GBE1 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.986A>C (p.Tyr329Ser) missense variant has been reported in multiple individuals with glycogen storage disease type IV or adult polyglucosan body disease, both in homozygous state and compound heterozygous state: p.Y329S/p.L224P, p.Y329S/p.R565Q, p.Y329S/c.2003delA, p.Y329C/p.N556Y (PMID: 20655781; 23034915). Functional studies showed the Y329S variant has 50% of GBE activity when compared to wild type (PMID: 8613547). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PS3, PM3_Strong, PP4. (less)
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Pathogenic
(Dec 01, 1998)
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no assertion criteria provided
Method: literature only
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GLYCOGEN STORAGE DISEASE IV, NONPROGRESSIVE HEPATIC
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023065.9
First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2022 |
Comment on evidence:
Glycogen Storage Disease IV In a Jewish female infant with the nonprogressive hepatic form of glycogen storage disease IV (GSD4; 232500), Bao et al. (1996) … (more)
Glycogen Storage Disease IV In a Jewish female infant with the nonprogressive hepatic form of glycogen storage disease IV (GSD4; 232500), Bao et al. (1996) found 2 missense mutations on separate alleles of the GBE1 gene: leu224-to-pro (L224P; 607839.0003) and tyr329-to-ser (Y329S). The L224P mutation resulted in complete loss of GBE1 activity, whereas the Y329S mutation resulted in loss of approximately 50% of GBE1 activity. Bao et al. (1996) detected the Y329S allele in another patient with the nonprogressive form of GSD IV but not in 35 unrelated controls or in patients with the more severe forms of GSD IV. The Y329S substitution resulted from an A-to-C transversion at nucleotide 1076. The second patient with the Y329S allele was 20 years old at the time of report and had normal liver function. Adult Polyglucosan Body Neuropathy In 7 Jewish patients with adult polyglucosan body neuropathy (APBN; 263570), Lossos et al. (1998) identified homozygosity for the Y329S mutation. The authors concluded that despite the very different phenotypes of APBN and GSD IV, they are allelic disorders. Mochel et al. (2012) identified the Y329S mutation in 35 (76%) of 50 patients with APBN, all of whom were of Ashkenazi Jewish origin. Thirteen of the patients carried the Y329S mutation in heterozygous state, but the gene was not exhaustively studied for other possible variants. Akman et al. (2015) performed follow-up of some of the heterozygous patients reported by Mochel et al. (2012). In a cohort of 16 patients of Ashkenazi Jewish descent who were initially found to be heterozygous for the Y329S mutation, Akman et al. (2015) found that 3 were compound heterozygous for Y329S, caused by a c.986A-C transversion in exon 7, and a c.671T-C transition, resulting in a leu224-to-pro (L224P; 607839.0003) substitution. The remaining 16 heterozygous patients carried a complex deep intronic del/ins mutation in intron 15 (607839.0020) that resulted in a truncated protein. Haplotype analysis suggested a founder effect for the deep intronic mutation. The mean GBE activity in compound heterozygotes was 8% of normal compared to 18% of normal in Y329S homozygotes. (less)
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Pathogenic
(Dec 01, 1998)
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no assertion criteria provided
Method: literature only
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ADULT POLYGLUCOSAN BODY NEUROPATHY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000196929.7
First in ClinVar: Jan 29, 2015 Last updated: Dec 31, 2022 |
Comment on evidence:
Glycogen Storage Disease IV In a Jewish female infant with the nonprogressive hepatic form of glycogen storage disease IV (GSD4; 232500), Bao et al. (1996) … (more)
Glycogen Storage Disease IV In a Jewish female infant with the nonprogressive hepatic form of glycogen storage disease IV (GSD4; 232500), Bao et al. (1996) found 2 missense mutations on separate alleles of the GBE1 gene: leu224-to-pro (L224P; 607839.0003) and tyr329-to-ser (Y329S). The L224P mutation resulted in complete loss of GBE1 activity, whereas the Y329S mutation resulted in loss of approximately 50% of GBE1 activity. Bao et al. (1996) detected the Y329S allele in another patient with the nonprogressive form of GSD IV but not in 35 unrelated controls or in patients with the more severe forms of GSD IV. The Y329S substitution resulted from an A-to-C transversion at nucleotide 1076. The second patient with the Y329S allele was 20 years old at the time of report and had normal liver function. Adult Polyglucosan Body Neuropathy In 7 Jewish patients with adult polyglucosan body neuropathy (APBN; 263570), Lossos et al. (1998) identified homozygosity for the Y329S mutation. The authors concluded that despite the very different phenotypes of APBN and GSD IV, they are allelic disorders. Mochel et al. (2012) identified the Y329S mutation in 35 (76%) of 50 patients with APBN, all of whom were of Ashkenazi Jewish origin. Thirteen of the patients carried the Y329S mutation in heterozygous state, but the gene was not exhaustively studied for other possible variants. Akman et al. (2015) performed follow-up of some of the heterozygous patients reported by Mochel et al. (2012). In a cohort of 16 patients of Ashkenazi Jewish descent who were initially found to be heterozygous for the Y329S mutation, Akman et al. (2015) found that 3 were compound heterozygous for Y329S, caused by a c.986A-C transversion in exon 7, and a c.671T-C transition, resulting in a leu224-to-pro (L224P; 607839.0003) substitution. The remaining 16 heterozygous patients carried a complex deep intronic del/ins mutation in intron 15 (607839.0020) that resulted in a truncated protein. Haplotype analysis suggested a founder effect for the deep intronic mutation. The mean GBE activity in compound heterozygotes was 8% of normal compared to 18% of normal in Y329S homozygotes. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Glycogen storage disease type IV
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001461485.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Glycogen storage disease, type IV
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000040490.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Two cases of a non-progressive hepatic form of glycogen storage disease type IV with atypical liver pathology. | Ichimoto K | Molecular genetics and metabolism reports | 2020 | PMID: 32455116 |
GBE1 Adult Polyglucosan Body Disease. | Adam MP | - | 2020 | PMID: 20301758 |
Novel GBE1 mutation in a Japanese family with adult polyglucosan body disease. | Harigaya Y | Neurology. Genetics | 2017 | PMID: 28265589 |
Alglucosidase alfa treatment alleviates liver disease in a mouse model of glycogen storage disease type IV. | Yi H | Molecular genetics and metabolism reports | 2016 | PMID: 27747161 |
A novel mouse model that recapitulates adult-onset glycogenosis type 4. | Orhan Akman H | Human molecular genetics | 2015 | PMID: 26385640 |
Structural basis of glycogen branching enzyme deficiency and pharmacologic rescue by rational peptide design. | Froese DS | Human molecular genetics | 2015 | PMID: 26199317 |
Deep intronic GBE1 mutation in manifesting heterozygous patients with adult polyglucosan body disease. | Akman HO | JAMA neurology | 2015 | PMID: 25665141 |
Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. | Fogel BL | JAMA neurology | 2014 | PMID: 25133958 |
Personalized genomic disease risk of volunteers. | Gonzalez-Garay ML | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 24082139 |
Polyglucosan neurotoxicity caused by glycogen branching enzyme deficiency can be reversed by inhibition of glycogen synthase. | Kakhlon O | Journal of neurochemistry | 2013 | PMID: 23607684 |
Adult polyglucosan body disease: Natural History and Key Magnetic Resonance Imaging Findings. | Mochel F | Annals of neurology | 2012 | PMID: 23034915 |
Progress and problems in muscle glycogenoses. | DiMauro S | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2011 | PMID: 22106711 |
Adult Polyglucosan Body Disease (APBD): Anaplerotic diet therapy (Triheptanoin) and demonstration of defective methylation pathways. | Roe CR | Molecular genetics and metabolism | 2010 | PMID: 20655781 |
Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene. | Lossos A | Annals of neurology | 1998 | PMID: 9851430 |
Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene. | Bao Y | The Journal of clinical investigation | 1996 | PMID: 8613547 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GBE1 | - | - | - | - |
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Text-mined citations for rs80338671 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.