The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Not predicted to affect natural splicing. Low nucleotide conservation. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. 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.
ClinVar Genomic variation as it relates to human health
NM_000083.3(CLCN1):c.1167-10T>C
Germline
Classification
Help
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.
(10)
Help
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/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000083.3(CLCN1):c.1167-10T>C
Variation ID: 462828 Accession: VCV000462828.42
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q34 7: 143332409 (GRCh38) [ NCBI UCSC ] 7: 143029502 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 26, 2017 Oct 20, 2024 Apr 4, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000083.3:c.1167-10T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000007.14:g.143332409T>C NC_000007.13:g.143029502T>C NG_009815.1:g.21284T>C - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000007.14:143332408:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| CLCN1 | - | - |
GRCh38 GRCh37 |
1399 | 1551 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
Jan 22, 2024 | RCV000540290.10 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 11, 2023 | RCV000711215.29 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 20, 2024 | RCV000987989.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 4, 2024 | RCV003992320.2 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myotonia, autosomal recessive form
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001137532.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Likely pathogenic
(Jan 31, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000841547.2
First in ClinVar: Oct 20, 2018 Last updated: Jan 26, 2021 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. … (more)
The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Not predicted to affect natural splicing. Low nucleotide conservation. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. 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)
|
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myotonia, autosomal recessive form
Congenital myotonia, autosomal dominant form
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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000636290.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change falls in intron 10 of the CLCN1 gene. It does not directly change the encoded amino acid sequence of the CLCN1 protein. … (more)
This sequence change falls in intron 10 of the CLCN1 gene. It does not directly change the encoded amino acid sequence of the CLCN1 protein. This variant is present in population databases (rs543120965, gnomAD 0.003%). This variant has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 18337730, 22094069, 22649220, 23739125, 29606556). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 462828). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Jul 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248206.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(May 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myotonia, autosomal recessive form
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934131.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: CLCN1 c.1167-10T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: CLCN1 c.1167-10T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 3' acceptor site. The variant allele was found at a frequency of 1.2e-05 in 251448 control chromosomes (gnomAD). c.1167-10T>C has been reported in the literature in multiple bi-allelic individuals affected with Myotonia congenita (examples: Trip_2008, Mazon_2012, Borklu-Yucel_2020, Orsini_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32140910, 22094069, 18337730, 32117024). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Oct 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003826834.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Feb 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myotonia, autosomal recessive form
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV004697550.1
First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024 |
|
|
|
Likely pathogenic
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myotonia, autosomal dominant form
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004810031.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
|
|
Pathogenic
(Sep 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005324935.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 31589614, 34426522, 32140910, 32117024, 32593548, 18337730, 32670189, 23739125, 23810313, 22649220, 22094069, 34529042, 29606556, 28427807) (less)
|
|
|
Pathogenic
(May 16, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Congenital myotonia, autosomal recessive form
Congenital myotonia, autosomal dominant form
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: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV004808390.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
Comment:
Comment:
This sequence change falls in intron 10 of the CLCN1 gene. It does not directly change the encoded amino acid sequence of the CLCN1 protein. This variant is present in population databases (rs543120965, gnomAD 0.003%). This variant has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 18337730, 22094069, 22649220, 23739125, 29606556). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 462828). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: CLCN1 c.1167-10T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 3' acceptor site. The variant allele was found at a frequency of 1.2e-05 in 251448 control chromosomes (gnomAD). c.1167-10T>C has been reported in the literature in multiple bi-allelic individuals affected with Myotonia congenita (examples: Trip_2008, Mazon_2012, Borklu-Yucel_2020, Orsini_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32140910, 22094069, 18337730, 32117024). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 31589614, 34426522, 32140910, 32117024, 32593548, 18337730, 32670189, 23739125, 23810313, 22649220, 22094069, 34529042, 29606556, 28427807)
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. |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Not predicted to affect natural splicing. Low nucleotide conservation. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. 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.
Comment:
This sequence change falls in intron 10 of the CLCN1 gene. It does not directly change the encoded amino acid sequence of the CLCN1 protein. This variant is present in population databases (rs543120965, gnomAD 0.003%). This variant has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 18337730, 22094069, 22649220, 23739125, 29606556). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 462828). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: CLCN1 c.1167-10T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 3' acceptor site. The variant allele was found at a frequency of 1.2e-05 in 251448 control chromosomes (gnomAD). c.1167-10T>C has been reported in the literature in multiple bi-allelic individuals affected with Myotonia congenita (examples: Trip_2008, Mazon_2012, Borklu-Yucel_2020, Orsini_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32140910, 22094069, 18337730, 32117024). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 31589614, 34426522, 32140910, 32117024, 32593548, 18337730, 32670189, 23739125, 23810313, 22649220, 22094069, 34529042, 29606556, 28427807)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical exome sequencing in neuromuscular diseases: an experience from Turkey. | Börklü-Yücel E | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2020 | PMID: 32140910 |
| CLCN1 Molecular Characterization in 19 South-Italian Patients With Dominant and Recessive Type of Myotonia Congenita. | Orsini C | Frontiers in neurology | 2020 | PMID: 32117024 |
| Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands. | Stunnenberg BC | Neuromuscular disorders : NMD | 2018 | PMID: 29606556 |
| Targeted Next Generation Sequencing in patients with Myotonia Congenita. | Ferradini V | Clinica chimica acta; international journal of clinical chemistry | 2017 | PMID: 28427807 |
| Muscle MRI reveals distinct abnormalities in genetically proven non-dystrophic myotonias. | Morrow JM | Neuromuscular disorders : NMD | 2013 | PMID: 23810313 |
| A large cohort of myotonia congenita probands: novel mutations and a high-frequency mutation region in exons 4 and 5 of the CLCN1 gene. | Brugnoni R | Journal of human genetics | 2013 | PMID: 23739125 |
| A new explanation for recessive myotonia congenita: exon deletions and duplications in CLCN1. | Raja Rayan DL | Neurology | 2012 | PMID: 22649220 |
| Screening for mutations in Spanish families with myotonia. Functional analysis of novel mutations in CLCN1 gene. | Mazón MJ | Neuromuscular disorders : NMD | 2012 | PMID: 22094069 |
| In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia. | Trip J | European journal of human genetics : EJHG | 2008 | PMID: 18337730 |
Text-mined citations for rs543120965 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.