ClinVar Genomic variation as it relates to human health
NM_000158.4(GBE1):c.986A>G (p.Tyr329Cys)
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.
Likely pathogenic(5); Uncertain significance(12)
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>G (p.Tyr329Cys)
Variation ID: 371439 Accession: VCV000371439.47
- 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 Jan 6, 2017 May 12, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000158.4:c.986A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000149.4:p.Tyr329Cys missense NC_000003.12:g.81642787T>C NC_000003.11:g.81691938T>C NG_011810.1:g.124014A>G - Protein change
- Y329C
- Other names
- NM_000158.4(GBE1):c.986A>G
- p.Tyr329Cys
- Canonical SPDI
- NC_000003.12:81642786:T:C
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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.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00029
Trans-Omics for Precision Medicine (TOPMed) 0.00053
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 |
982 | 998 |
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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Conflicting interpretations of pathogenicity (9) |
criteria provided, conflicting classifications
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Mar 26, 2024 | RCV000410814.26 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Nov 1, 2022 | RCV000490240.20 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV000529291.9 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 22, 2021 | RCV001145097.8 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 23, 2020 | RCV001172459.12 |
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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Likely pathogenic
(Oct 31, 2016)
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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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Counsyl
Accession: SCV000487021.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Apr 27, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001305737.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Adult polyglucosan body disease
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001305738.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jun 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000594937.2
First in ClinVar: Jan 06, 2017 Last updated: Jun 12, 2020 |
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Uncertain significance
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Adult polyglucosan body disease
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001810441.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Uncertain significance
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type IV
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001810439.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Uncertain significance
(Jul 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984267.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021
Comment:
The Tyr329Cys missense variant in the GBE1 gene has been previously reported in five individuals with adult polyglucosan body disease who carried a second missense … (more)
The Tyr329Cys missense variant in the GBE1 gene has been previously reported in five individuals with adult polyglucosan body disease who carried a second missense variant (Asn556Tyr) although phase of these variants was described as compound heterozygous in only one individual (PMID: 23034915). All five patients were reported to have reduced GBE enzymatic activity (PMID: 23034915). This variant was also identified in the homozygous state in one patient with glycogen storage disease (PMID: 30293248). Another missense variant at the same codon (Tyr329Ser) is commonly observed within affected Ashkenazi Jews (PMID: 23034915). However the Tyr329Cys variant was also identified in 27/30586 (0.08%) South Asian alleles including one homozygote in the Genome Aggregation Database (gnomAD). It was also identified in 10/1976 Middle Eastern alleles including one homozygote in the Greater Middle East (GNE) Variome Database. Furthermore this variant is reportedly present in 3 presumably healthy homozygous individuals tested at another clinical laboratory (ClinVar ID: 371439). Computational prediction tools and conservation analyses suggest an impact to protein function though this information is not predictive enough to confirm out pathogenicity. In summary more information is needed to determine the clinical significance of this variant. (less)
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Uncertain significance
(Jan 27, 2022)
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criteria provided, single submitter
Method: curation
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Glycogen storage disease, type IV
(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: SCV002097105.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment:
The p.Tyr329Cys variant in GBE1 has been reported in 6 individuals with GBE1-related disorders (PMID: 30293248, 23034915) and has been identified in 0.09% (27/30586) of … (more)
The p.Tyr329Cys variant in GBE1 has been reported in 6 individuals with GBE1-related disorders (PMID: 30293248, 23034915) and has been identified in 0.09% (27/30586) of South Asian chromosomes by the Genome Aggregation Database, including one homozygote (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#: 371439) and has been interpreted as likely pathogenic by Counsyl, Invitae, and Women's Health and Genetics (Laboratory Corporation of America, LabCorp), and as uncertain significance by GeneDx, Illumina Clinical Services Laboratory (Illumina), Genetic Services Laboratory (University of Chicago), Nilou-Genome Lab, and Al Jalila Children's Genomics Center (Al Jalila Childrens Speciality Hospital). Of the 6 affected individuals, 1 of those were homozygote, which increases the likelihood that the p.Tyr329Cys variant is pathogenic (PMID: 30293248). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Tyr329Ser, has been reported in association with disease in (the literature and ClinVar), supporting that a change at this position may not be tolerated (PMID: 8613547, 9851430, 20655781, 23034915, 25133958, 25665141, 33332610, 26385640/Variation ID: 2777). In summary, the clinical significance of the p.Tyr329Cys variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3_supporting, PM5 (Richards 2015). (less)
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Likely pathogenic
(May 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type IV
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557032.2
First in ClinVar: Aug 04, 2022 Last updated: Dec 17, 2022 |
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Uncertain significance
(Jun 27, 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: SCV000577621.7
First in ClinVar: May 22, 2017 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 31207142, 31319225, 31209396, 8613547, 23034915, 30293248, 34426522, 34297361) (less)
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Uncertain significance
(Jul 15, 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: SCV004198699.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Sep 30, 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: SCV003832932.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jan 29, 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: SCV000626777.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Mar 15, 2024)
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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: SCV001338529.6
First in ClinVar: Jun 18, 2020 Last updated: May 12, 2024 |
Comment:
Variant summary: GBE1 c.986A>G (p.Tyr329Cys) 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>G (p.Tyr329Cys) 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 0.00045 in 248464 control chromosomes, predominantly at a frequency of 0.00088 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in GBE1 causing Glycogen Storage Disease, Type IV (0.00045 vs 0.0013), allowing no conclusion about variant significance. c.986A>G has been reported in the literature in five individuals affected with Adult Polyglucosan Body Disease who also carried a second variant (N556Y) (Mochel_2012). The variant has also been reported in at least two individuals with glycogen storage disease, one homozygote and one heterozygote without a reported second mutation (Nair_2018, Isik_2019). In addition, another missense variant at the same codon (Y329S) has been classified as pathogenic and is a common mutation within affected Ashkenazi Jewish patients (Mochel_2012), suggesting the tyrosine residue at position 329 is critical for GBE1 protein function. These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 31207142, 31980526, 31209396, 31319225, 34426522, 27528516, 23034915, 30293248, 28716262). ClinVar contains an entry for this variant (Variation ID: 371439). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Nov 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002563778.11
First in ClinVar: Aug 23, 2022 Last updated: May 12, 2024 |
Comment:
GBE1: PM2:Supporting
Number of individuals with the variant: 2
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Uncertain significance
(Mar 26, 2024)
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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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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806797.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type IV
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005042802.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Comment:
The missense c.986A>G p.Tyr329Cys variant in the GBE1 gene has been reported in 6 individuals with GBE1-related disorders Nair, Pratibha et al., 2018. This variant … (more)
The missense c.986A>G p.Tyr329Cys variant in the GBE1 gene has been reported in 6 individuals with GBE1-related disorders Nair, Pratibha et al., 2018. This variant is reported with the allele frequency 0.04% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic/ Uncertain Significance multiple submissions. The amino acid Tyrosine at position 329 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Tyr329Cys in GBE1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. (less)
Clinical Features:
Abnormal metabolism (present)
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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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The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Clinical utility of a targeted next generation sequencing panel in severe and pediatric onset Mendelian diseases. | Isik E | European journal of medical genetics | 2019 | PMID: 31319225 |
Recessive gene disruptions in autism spectrum disorder. | Doan RN | Nature genetics | 2019 | PMID: 31209396 |
Investigation of new candidate genes in retinoblastoma using the TruSight One "clinical exome" gene panel. | Akdeniz D | Molecular genetics & genomic medicine | 2019 | PMID: 31207142 |
Contribution of next generation sequencing in pediatric practice in Lebanon. A Study on 213 cases. | Nair P | Molecular genetics & genomic medicine | 2018 | PMID: 30293248 |
New genetic causes for complex hereditary spastic paraplegia. | Souza PVS | Journal of the neurological sciences | 2017 | PMID: 28716262 |
Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias. | Marelli C | Human mutation | 2016 | PMID: 27528516 |
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 |
Adult polyglucosan body disease: Natural History and Key Magnetic Resonance Imaging Findings. | Mochel F | Annals of neurology | 2012 | PMID: 23034915 |
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 |
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Text-mined citations for rs80338671 ...
HelpRecord last updated May 12, 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.