NM_000100.4(CSTB):c.67-1G>C AND Unverricht-Lundborg syndrome

Germline classification:: Conflicting interpretations of pathogenicity (9 submissions)
Last evaluated:: Apr 29, 2021
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000008903.35

Allele description [Variation Report for NM_000100.4(CSTB):c.67-1G>C]

NM_000100.4(CSTB):c.67-1G>C

Gene:

CSTB:cystatin B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.3

Genomic location:

Preferred name:

NM_000100.4(CSTB):c.67-1G>C

HGVS:

NC_000021.9:g.43774760C>G
NG_011545.1:g.6619G>C
NM_000100.4:c.67-1G>CMANE SELECT
LRG_485t1:c.67-1G>C
LRG_485:g.6619G>C
NC_000021.8:g.45194641C>G
NM_000100.2:c.67-1G>C
NM_000100.3:c.67-1G>C

Note:

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.

Nucleotide change:

IVS1, G-C, -1

Links:

OMIM: 601145.0001; dbSNP: rs147484110

NCBI 1000 Genomes Browser:

rs147484110

Molecular consequence:

NM_000100.4:c.67-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: Unverricht-Lundborg syndrome
Synonyms:: Epilepsy, progressive myoclonus 1; Myoclonic epilepsy of Unverricht and Lundborg; Epilepsy, progressive myoclonic type 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009698; MedGen: C0751785; Orphanet: 308; OMIM: 254800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000029113	OMIM	no assertion criteria provided	Pathogenic (Mar 22, 1996)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000195824	GeneReviews	no classification provided	not provided	germline	literature only
SCV000247125	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 6, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000328698	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha	criteria provided, single submitter (HA_assertions_20161101)	Pathogenic (Oct 13, 2016)	unknown	research	Citation Link,
SCV000893558	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000915956	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Aug 31, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23205931, 8596935, 17003839, 9360639 Citation Link,
SCV002019757	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 26, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002099167	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (Apr 29, 2021)	germline	clinical testing	Citation Link,
SCV002547301	GenomeConnect - Brain Gene Registry	no classification provided	not provided	paternal	phenotyping only

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	paternal	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	1	not provided	not provided	1	not provided	research

Citations

PubMed

Electroclinical presentation and genotype-phenotype relationships in patients with Unverricht-Lundborg disease carrying compound heterozygous CSTB point and indel mutations.

Canafoglia L, Gennaro E, Capovilla G, Gobbi G, Boni A, Beccaria F, Viri M, Michelucci R, Agazzi P, Assereto S, Coviello DA, Di Stefano M, Rossi Sebastiano D, Franceschetti S, Zara F.

Epilepsia. 2012 Dec;53(12):2120-7. doi: 10.1111/j.1528-1167.2012.03718.x. Erratum in: Epilepsia. 2013 Jul;54(7):1333.

PubMed [citation]

PMID:: 23205931

Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1)

Pennacchio LA, Lehesjoki AE, Stone NE, Willour VL, Virtaneva K, Miao J, D'Amato E, Ramirez L, Faham M, Koskiniemi M, Warrington JA, Norio R, de la Chapelle A, Cox DR, Myers RM.

Science. 1996 Mar 22;271(5256):1731-4.

PubMed [citation]

PMID:: 8596935

See all PubMed Citations (5)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000029113.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000195824.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV000247125.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha, SCV000328698.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893558.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000915956.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002019757.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From New York Genome Center - CSER-NYCKidSeq, SCV002099167.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From GenomeConnect - Brain Gene Registry, SCV002547301.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

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/.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 19, 2024

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