ClinVar Genomic variation as it relates to human health
NM_004366.6(CLCN2):c.1709G>A (p.Trp570Ter)
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_004366.6(CLCN2):c.1709G>A (p.Trp570Ter)
Variation ID: 100629 Accession: VCV000100629.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q27.1 3: 184354113 (GRCh38) [ NCBI UCSC ] 3: 184071901 (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 Feb 26, 2014 Feb 14, 2024 Sep 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004366.6:c.1709G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004357.3:p.Trp570Ter nonsense NM_001171087.3:c.1658G>A NP_001164558.1:p.Trp553Ter nonsense NM_001171088.3:c.1577G>A NP_001164559.1:p.Trp526Ter nonsense NM_001171089.3:c.1709G>A NP_001164560.1:p.Trp570Ter nonsense NC_000003.12:g.184354113C>T NC_000003.11:g.184071901C>T NG_016422.1:g.12491G>A - Protein change
- W570*, W553*, W526*
- Other names
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- Canonical SPDI
- NC_000003.12:184354112:C:T
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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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CLCN2 | - | - |
GRCh38 GRCh37 |
439 | 487 |
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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 21, 2022 | RCV000087029.15 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 16, 2022 | RCV000599144.16 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 5, 2021 | RCV002490754.8 | |
Pathogenic (2) |
criteria provided, single submitter
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Sep 29, 2023 | RCV003326348.6 |
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
(Feb 13, 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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GeneDx
Accession: SCV000709908.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Comment:
The W570X variant in the CLCN2 gene has been reported previously as an apparently homozygous pathogenic variant in two unrelated individuals with adult-onset leukodystrophy (Depienne … (more)
The W570X variant in the CLCN2 gene has been reported previously as an apparently homozygous pathogenic variant in two unrelated individuals with adult-onset leukodystrophy (Depienne et al., 2013). W570X has also been reported in an individual with idiopathic generalized epilepsy; however, no further information was provided (Klassen et al., 2011). Functional studies show that W570X results in decreased protein expression and abnormal protein localization (Depienne et al., 2013). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W570X variant is observed in 8/276228 (0.003%) alleles in large population cohorts (Lek et al., 2016). We interpret W570X as a pathogenic variant. (less)
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Pathogenic
(Feb 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy with mild cerebellar ataxia and white matter edema
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002103746.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: CLCN2 c.1709G>A (p.Trp570X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: CLCN2 c.1709G>A (p.Trp570X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations upstream and downstream of this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 2.5e-05 in 281446 control chromosomes (gnomAD). c.1709G>A has been reported in the literature in two unrelated homozygous individuals affected with leukoencephalopathy (Depienne_2013). This publication also reported experimental evidence and demonstrated decreased mRNA levels in patient derived fibroblasts, consistent with an incomplete nonsense-mediated mRNA decay; in addition, the truncated protein, when expressed in transiently transfected COS7 cells, had an aberrant subcellular localization (Depienne_2013). The variant allele has also been reported to be found in a cohort of idiopathic epilepsy patients, however no genotype info was provided (Klassen_2011). Four submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Oct 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial hyperaldosteronism type II
Epilepsy, idiopathic generalized, susceptibility to, 11 Leukoencephalopathy with mild cerebellar ataxia and white matter edema
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002796699.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Epilepsy, idiopathic generalized, susceptibility to, 11
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004183543.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Jun 16, 2021)
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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: SCV002017371.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Aug 16, 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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Invitae
Accession: SCV002228060.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 100629). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 100629). This premature translational stop signal has been observed in individual(s) with epilepsy (PMID: 21703448). This variant is present in population databases (rs201330912, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Trp570*) in the CLCN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLCN2 are known to be pathogenic (PMID: 23707145). (less)
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy with mild cerebellar ataxia and white matter edema
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001136652.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Jul 01, 2013)
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no assertion criteria provided
Method: literature only
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LEUKOENCEPHALOPATHY WITH ATAXIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000119843.1
First in ClinVar: Feb 26, 2014 Last updated: Feb 26, 2014 |
Comment on evidence:
In 2 unrelated patients from North Africa with adult-onset leukoencephalopathy with ataxia (LKPAT; 615651) Depienne et al. (2013) identified a homozygous c.1709G-A transition in exon … (more)
In 2 unrelated patients from North Africa with adult-onset leukoencephalopathy with ataxia (LKPAT; 615651) Depienne et al. (2013) identified a homozygous c.1709G-A transition in exon 15 of the CLCN2 gene, resulting in a trp570-to-ter (W570X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the HapMap Project or 1000 Genomes Project databases or in controls. Patient fibroblasts showed decreased mutant mRNA, consistent with nonsense-mediated mRNA decay and suggesting a loss of function. (less)
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Pathogenic
(Apr 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Epilepsy, idiopathic generalized, susceptibility to, 11
Affected status: yes
Allele origin:
germline
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Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927883.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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not provided
(-)
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no classification provided
Method: literature only
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Leukoencephalopathy with mild cerebellar ataxia and white matter edema
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000256592.2
First in ClinVar: Nov 09, 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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CLCN2-Related Leukoencephalopathy. | Adam MP | - | 2021 | PMID: 26539602 |
Frequency spectrum of rare and clinically relevant markers in multiethnic Indian populations (ClinIndb): A resource for genomic medicine in India. | Narang A | Human mutation | 2020 | PMID: 32906206 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. | Depienne C | The Lancet. Neurology | 2013 | PMID: 23707145 |
Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. | Klassen T | Cell | 2011 | PMID: 21703448 |
Text-mined citations for rs201330912 ...
HelpRecord last updated Jun 02, 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.