ClinVar Genomic variation as it relates to human health
NM_000100.4(CSTB):c.67-1G>C
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(12); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000100.4(CSTB):c.67-1G>C
Variation ID: 8395 Accession: VCV000008395.42
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.3 21: 43774760 (GRCh38) [ NCBI UCSC ] 21: 45194641 (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 28, 2015 May 1, 2024 Dec 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000100.4:c.67-1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NC_000021.9:g.43774760C>G NC_000021.8:g.45194641C>G NG_011545.1:g.6619G>C LRG_485:g.6619G>C LRG_485t1:c.67-1G>C - Protein change
- Other names
- IVS1, G-C, -1
- Canonical SPDI
- NC_000021.9:43774759:C: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 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00010
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
The Genome Aggregation Database (gnomAD), exomes 0.00015
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00027
Trans-Omics for Precision Medicine (TOPMed) 0.00028
- Comment on variant
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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CSTB | - | - |
GRCh38 GRCh37 |
112 | 276 |
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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Apr 29, 2021 | RCV000008903.35 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2022 | RCV000187278.24 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2018 | RCV000622443.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 17, 2023 | RCV000638304.15 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001003638.9 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001254919.9 |
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
(Dec 06, 2014)
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criteria provided, single submitter
Method: clinical testing
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Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000247125.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Sep 15, 2015)
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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: SCV000335378.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Jul 26, 2019)
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criteria provided, single submitter
Method: clinical testing
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Unverricht-Lundborg syndrome
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019757.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Unverricht-Lundborg syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893558.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Aug 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Unverricht-Lundborg syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915956.1
First in ClinVar: May 24, 2019 Last updated: May 24, 2019 |
Comment:
The CSTB c.67-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Across a … (more)
The CSTB c.67-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Across a selection of the literature, the c.67-1G>C variant has been identified in a compound heterozygous state in at least seven individuals with Unverricht-Lundborg disease (ULD) from six families and in one additional family where zygosity was not specified (Pennacchio et al. 1996; Joensuu et al. 2007 and Canafoglia et al. 2012). The c.67-1G>C variant was most commonly identified in a compound heterozygous state with the expanded dodecamer repeat variant, which is the most common pathogenic variant associated with ULD. Bespalova et al. (1997) analyzed mRNA transcripts from heterozygous individuals carrying the c.67-1G>C variant. RT-PCR of total mRNA showed an aberrant, shorter transcript created as a result of skipping of exon 2, confirming that the c.67-1G>C variant disrupts normal splicing and results in expression of a truncated protein. The c.67-1G>C variant was absent from at least 95 unaffected control individuals and is reported at a frequency of 0.000347 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the c.67-1G>C variant is classified as pathogenic for Unverricht-Lundborg disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Encephalopathy
Microcephaly Cerebral dysmyelination (Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001431008.1
First in ClinVar: Sep 03, 2020 Last updated: Sep 03, 2020 |
Sex: male
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Uncertain significance
(Apr 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Unverricht-Lundborg syndrome
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002099167.1 First in ClinVar: Feb 26, 2022 Last updated: Feb 26, 2022 |
Clinical Features:
Seizure (present)
Secondary finding: no
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Pathogenic
(Oct 13, 2016)
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criteria provided, single submitter
Method: research
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Unverricht-Lundborg syndrome
Affected status: yes
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000328698.3 First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Generalized hypotonia (present) , Global developmental delay (present) , Microcephaly (present) , Failure to thrive (present) , Abnormal facial shape (present)
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Pathogenic
(Jan 10, 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: SCV000240860.18
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Published studies in a patient who was compound heterozygous for this variant and an expansion variant demonstrated that the level of CSTB mRNA was diminished … (more)
Published studies in a patient who was compound heterozygous for this variant and an expansion variant demonstrated that the level of CSTB mRNA was diminished compared to controls, and no protein was detected on Western blot (Joensuu et al., 2007); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 18325013, 23205931, 9360639, 9054946, 25525159, 20301321, 9012407, 17003839, 29915382, 32581362, 8596935, 31589614) (less)
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Pathogenic
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010262.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Pathogenic
(Apr 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV000613026.4
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024 |
Comment:
This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population … (more)
This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
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Pathogenic
(Dec 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Progressive myoclonic epilepsy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000759798.7
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 1 of the CSTB gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects an acceptor splice site in intron 1 of the CSTB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs147484110, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with Unverricht-Lundborg disease (PMID: 8596935, 9012407, 9054946, 23205931). This variant is also known as 1924G>C. ClinVar contains an entry for this variant (Variation ID: 8395). Studies have shown that disruption of this splice site results in skipping of exon 2, but is expected to preserve the integrity of the reading-frame (PMID: 9360639, 17003839, 23205931). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742065.4
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The c.67-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 2 of the CSTB gene. This mutation … (more)
The c.67-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 2 of the CSTB gene. This mutation was identified in trans with other pathogenic CSTB alterations in multiple unrelated individuals with progressive myoclonus epilepsy; it was shown to result in a misspliced mRNA product with an aberrant CSTB product lacking 33 amino acids, p.V23_K56del (Pennacchio LA et al. Science, 1996 Mar;271:1731-4; Joensuu T et al. Eur. J. Hum. Genet., 2007 Feb;15:185-93; Canafoglia L et al. Epilepsia, 2012 Dec;53:2120-7). Analysis of cells from affected patients demonstrated reduced mRNA and protein levels compared to wild type (Joensuu T et al. Eur. J. Hum. Genet., 2007 Feb;15:185-93; Canafoglia L et al. Epilepsia, 2012 Dec;53:2120-7). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
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Pathogenic
(Mar 22, 1996)
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no assertion criteria provided
Method: literature only
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MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029113.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 07, 2019 |
Comment on evidence:
By complete sequencing of the cystatin B gene in affected members of 4 families with myoclonic epilepsy of Unverricht and Lundborg (EPM1A; 254800), Pennacchio et … (more)
By complete sequencing of the cystatin B gene in affected members of 4 families with myoclonic epilepsy of Unverricht and Lundborg (EPM1A; 254800), Pennacchio et al. (1996) identified 2 different mutations in the cystatin B gene. One of these found in an American family was a G-to-C transversion at the last nucleotide of intron 1, altering the 3-prime splice site AG to AC. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Dyskinesia
Chorea
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162065.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: female
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not provided
(-)
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no classification provided
Method: phenotyping only
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Unverricht-Lundborg syndrome
Affected status: unknown
Allele origin:
paternal
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GenomeConnect - Brain Gene Registry
Accession: SCV002547301.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant interpreted as Pathogenic and reported on 02-23-2021 by lab or GTR ID 239772. Assertions are reported exactly as they appear on the patient provided … (more)
Variant interpreted as Pathogenic and reported on 02-23-2021 by lab or GTR ID 239772. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Clinical Features:
Hypermetropia (present) , Abnormality of the nervous system (present) , Abnormality of coordination (present) , EEG abnormality (present) , Hypertonia (present) , Generalized hypotonia (present) … (more)
Hypermetropia (present) , Abnormality of the nervous system (present) , Abnormality of coordination (present) , EEG abnormality (present) , Hypertonia (present) , Generalized hypotonia (present) , Seizure (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Method: Exome Sequencing
Testing laboratory: PreventionGenetics,PreventionGenetics
Date variant was reported to submitter: 2021-02-23
Testing laboratory interpretation: Pathogenic
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not provided
(-)
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no classification provided
Method: literature only
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Unverricht-Lundborg syndrome
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000195824.2
First in ClinVar: Oct 11, 2015 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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Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
Progressive Myoclonic Epilepsy Type 1. | Adam MP | - | 2020 | PMID: 20301321 |
Electroclinical presentation and genotype-phenotype relationships in patients with Unverricht-Lundborg disease carrying compound heterozygous CSTB point and indel mutations. | Canafoglia L | Epilepsia | 2012 | PMID: 23205931 |
G to C transversion at a splice acceptor site causes exon skipping in the cystatin B gene. | Bespalova IN | Mutation research | 1997 | PMID: 9360639 |
Unstable insertion in the 5' flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1. | Lafrenière RG | Nature genetics | 1997 | PMID: 9054946 |
Identification of mutations in cystatin B, the gene responsible for the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1). | Lalioti MD | American journal of human genetics | 1997 | PMID: 9012407 |
Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1). | Pennacchio LA | Science (New York, N.Y.) | 1996 | PMID: 8596935 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CSTB | - | - | - | - |
Text-mined citations for rs147484110 ...
HelpRecord last updated May 01, 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 8596935 Fig. 4 in the figure to determine the location of this allele on the current reference sequence.