ClinVar Genomic variation as it relates to human health
NM_000158.4(GBE1):c.760A>G (p.Thr254Ala)
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.
Pathogenic(3); Likely pathogenic(3); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000158.4(GBE1):c.760A>G (p.Thr254Ala)
Variation ID: 374517 Accession: VCV000374517.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p12.2 3: 81646414 (GRCh38) [ NCBI UCSC ] 3: 81695565 (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 30, 2017 Oct 26, 2024 Mar 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000158.4:c.760A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000149.4:p.Thr254Ala missense NC_000003.12:g.81646414T>C NC_000003.11:g.81695565T>C NG_011810.1:g.120387A>G - Protein change
- T254A
- Other names
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NM_000158.4(GBE1):c.760A>G
p.Thr254Ala
- Canonical SPDI
- NC_000003.12:81646413: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00007
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
1004 | 1020 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (3) |
criteria provided, conflicting classifications
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Sep 20, 2023 | RCV000416121.30 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Mar 30, 2024 | RCV001147053.15 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 28, 2023 | RCV001147052.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 2, 2024 | RCV001245740.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 20, 2021 | RCV001584110.3 |
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
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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
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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
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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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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: SCV001307825.1
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: SCV001307824.1
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
(Aug 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001821319.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Variant summary: GBE1 c.760A>G (p.Thr254Ala) results in a non-conservative amino acid change located in the Glycosyl hydrolase, family 13, catalytic domain of the encoded protein … (more)
Variant summary: GBE1 c.760A>G (p.Thr254Ala) results in a non-conservative amino acid change located in the Glycosyl hydrolase, family 13, catalytic domain 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 5.4e-05 in 242554 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GBE1 causing Glycogen Storage Disease, Type IV (5.4e-05 vs 0.0013), allowing no conclusion about variant significance. c.760A>G has been reported in the literature in two individuals affected with Glycogen Storage Disease, Type IV who have reported second mutations (Schene_2018) along with one patient who had only one mutation reported (Said_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two classified as VUS while one classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(Oct 26, 2021)
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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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061657.2
First in ClinVar: Jan 22, 2022 Last updated: Feb 02, 2022 |
Comment:
PM2
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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: SCV002097116.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment:
The p.Thr254Ala variant in GBE1 has been reported in 2 individuals with glycogen storage disease type IV (GSD IV) (PMID: 30569318), segregated with disease in … (more)
The p.Thr254Ala variant in GBE1 has been reported in 2 individuals with glycogen storage disease type IV (GSD IV) (PMID: 30569318), segregated with disease in 1 individual from 1 family (PMID: 33332610) and has been identified in 0.01% (13/111154) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs770427750). 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. Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Gly264Glu variant is pathogenic (VariationID: 208584; PMID: 30569318). This variant has also been reported in ClinVar (Variation ID#: 374517) and has been interpreted as likely pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen, and as a variant of uncertain significance by Illumina Clinical Services Laboratory (Illumina), Invitae, GeneDx, and Women's Health and Genetics (Laboratory Corporation of America, LabCorp). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Thr254Ala variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3 (Richards 2015). (less)
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Likely pathogenic
(Aug 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type IV
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581806.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM3_STR, PS4_MOD, PS3_SUP, PM2_SUP, PP3
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Number of individuals with the variant: 2
Sex: female
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Likely pathogenic
(Sep 20, 2023)
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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: SCV001793167.3
First in ClinVar: Aug 21, 2021 Last updated: Sep 30, 2023 |
Comment:
Observed heterozygous in an individual with glycogen storage disease type IV, however no second GBE1 variant was identified (Said et al., 2016); Not observed at … (more)
Observed heterozygous in an individual with glycogen storage disease type IV, however no second GBE1 variant was identified (Said et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); 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: 20058079, 33332610, 30228975, 27243974, 27107456, 36628840, 30569318, 36830903) (less)
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Pathogenic
(Jan 02, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001419045.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 254 of the GBE1 protein (p.Thr254Ala). … (more)
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 254 of the GBE1 protein (p.Thr254Ala). This variant is present in population databases (rs770427750, gnomAD 0.009%). This missense change has been observed in individual(s) with glycogen storage disease IV (PMID: 30569318, 33332610). ClinVar contains an entry for this variant (Variation ID: 374517). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBE1 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Sep 01, 2018)
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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: SCV000493291.33
First in ClinVar: Jan 30, 2017 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Sep 28, 2023)
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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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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004100752.2
First in ClinVar: Nov 04, 2023 Last updated: Apr 15, 2024 |
Comment:
Criteria applied: PM3_VSTR,PM2_SUP,PP3
Clinical Features:
Leukodystrophy (present) , Dementia (present)
Sex: male
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Pathogenic
(Mar 30, 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:
unknown
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Baylor Genetics
Accession: SCV004198660.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(Apr 02, 2021)
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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: SCV002082387.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Likely pathogenic
(Jun 01, 2022)
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no assertion criteria provided
Method: provider interpretation
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Glycogen storage disease, type IV
Affected status: yes
Allele origin:
inherited
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Solve-RD Consortium
Accession: SCV005091243.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
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Comment:
Variant confirmed as disease-causing by referring clinical team
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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 potential of dietary treatment in patients with glycogen storage disease type IV. | Derks TGJ | Journal of inherited metabolic disease | 2021 | PMID: 33332610 |
Glycogen Storage Disease Type IV: A Rare Cause for Neuromuscular Disorders or Often Missed? | Schene IF | JIMD reports | 2019 | PMID: 30569318 |
Analysis of GBE1 mutations via protein expression studies in glycogen storage disease type IV: A report on a non-progressive form with a literature review. | Iijima H | Molecular genetics and metabolism reports | 2018 | PMID: 30228975 |
Targeted Next Generation Sequencing in Patients with Inborn Errors of Metabolism. | Yubero D | PloS one | 2016 | PMID: 27243974 |
A novel GBE1 gene variant in a child with glycogen storage disease type IV. | Said SM | Human pathology | 2016 | PMID: 27107456 |
Glycogen storage disease type IV: novel mutations and molecular characterization of a heterogeneous disorder. | Li SC | Journal of inherited metabolic disease | 2010 | PMID: 20058079 |
Text-mined citations for rs770427750 ...
HelpRecord last updated Oct 27, 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.