ClinVar Genomic variation as it relates to human health
NM_000158.4(GBE1):c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT
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.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT
Variation ID: 225145 Accession: VCV000225145.7
- Type and length
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Indel, 19 bp
- Location
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Cytogenetic: 3p12.2 3: 81493813-81493821 (GRCh38) [ NCBI UCSC ] 3: 81542964-81542972 (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 14, 2016 Dec 24, 2023 Jan 27, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000158.4:c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000003.12:g.81493813_81493821delinsACCTGTCATGTAAAAAACA NC_000003.11:g.81542964_81542972delinsACCTGTCATGTAAAAAACA NG_011810.1:g.272980_272988delinsTGTTTTTTACATGACAGGT - Protein change
- Other names
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- Canonical SPDI
- NC_000003.12:81493812:CCACCACAC:ACCTGTCATGTAAAAAACA
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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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- Comment on variant
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 |
982 | 998 |
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
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
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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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Pathogenic (1) |
no assertion criteria provided
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Apr 11, 2016 | RCV000210799.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 11, 2021 | RCV001775673.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2022 | RCV001526450.5 |
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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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: SCV001736862.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Number of individuals with the variant: 1
Clinical Features:
Neurogenic bladder (present) , Urinary incontinence (present) , Optic atrophy (present) , Night blindness (present) , Cerebellar atrophy (present) , Bicuspid aortic valve (present) , … (more)
Neurogenic bladder (present) , Urinary incontinence (present) , Optic atrophy (present) , Night blindness (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
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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: SCV002097125.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment:
The c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT variant in GBE1 has been reported in 16 individuals with adult polyglucosan body disease (APBD) (PMID: 25665141), but data from large population studies … (more)
The c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT variant in GBE1 has been reported in 16 individuals with adult polyglucosan body disease (APBD) (PMID: 25665141), but data from large population studies is insufficient to assess the frequency of this variant. Of the 16 affected individuals, all were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT variant is pathogenic (VariationID: 2777; PMID: 25665141). This variant has also been reported in ClinVar (Variation ID#: 225145) and has been interpreted as likely pathogenic or pathogenic by OMIM, GeneDx, and the Undiagnosed Diseases Network (NIH). In vitro functional studies provide some evidence that the c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT variant may impact protein function (PMID: 25665141). However, these types of assays may not accurately represent biological function. 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 APBD. ACMG/AMP Criteria applied: PS3_moderate, PM3_very-strong, PP3(Richards 2015). (less)
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Likely pathogenic
(Aug 11, 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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GeneDx
Accession: SCV002013345.2
First in ClinVar: Nov 12, 2021 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports a deleterious effect on splicing; No data available from control populations to assess the frequency of this variant This variant is … (more)
In silico analysis supports a deleterious effect on splicing; No data available from control populations to assess the frequency of this variant This variant is associated with the following publications: (PMID: 25665141) (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: SCV004190170.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
The variant in the GBE1 gene, c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT, is a deep intronic insertion/deletion. This variant results in a sequence of nine intronic nucleotides being removed and … (more)
The variant in the GBE1 gene, c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT, is a deep intronic insertion/deletion. This variant results in a sequence of nine intronic nucleotides being removed and replaced by 20 nucleotides containing an mRNA splice acceptor. It has been found in trans with the c.986A>C variant in 16 patients of Ashkenazi Jewish descent with adult polyglucosan body disease (PMID: 25665141). PCR analysis showed that this variant caused the splicing of exon 15 into an ectopic splice acceptor site, creating an abnormal exon 16 with a new stop codon. The mean GBE activity in compound heterozygotes was 8% of normal compared to 18% of normal in c.986A>C homozygotes, indicating the truncated protein product is unstable (PMID: 25665141). (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.986A>C
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Pathogenic
(Apr 11, 2016)
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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: SCV000266856.1
First in ClinVar: Apr 14, 2016 Last updated: Apr 14, 2016 |
Comment on evidence:
In 13 patients of Ashkenazi Jewish descent with adult polyglucosan body neuropathy (APBN; 263570), Akman et al. (2015) identified compound heterozygous mutations in the GBE1 … (more)
In 13 patients of Ashkenazi Jewish descent with adult polyglucosan body neuropathy (APBN; 263570), Akman et al. (2015) identified compound heterozygous mutations in the GBE1 gene: in addition to the common founder Y329S mutation (607839.0002), all patients carried a complex deep intronic ins/del mutation in intron 15 (IVS15, +5289_5297del9ins20), resulting in an unstable truncated protein. PCR analysis showed that the abnormal sequence resulted in the splicing of exon 15 into an ectopic splice acceptor site, creating an abnormal exon 16 with a new stop codon. Haplotype analysis was consistent with 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, but there was no obvious difference in phenotype. There were no homozygotes for the deep intronic mutation, suggesting that homozygosity for the mutation may be prenatal lethal. Akman et al. (2015) noted that the mutation was missed by whole-genome sequencing, emphasizing potential pitfalls in genetic diagnostics using this method. (less)
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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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Deep intronic GBE1 mutation in manifesting heterozygous patients with adult polyglucosan body disease. | Akman HO | JAMA neurology | 2015 | PMID: 25665141 |
Text-mined citations for rs869320698 ...
HelpRecord last updated Mar 30, 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.
NCBI staff reviewed the sequence information reported in PubMed 25665141 to determine the location of this allele on the current reference sequence.