ClinVar Genomic variation as it relates to human health
NM_000083.3(CLCN1):c.1444G>A (p.Gly482Arg)
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_000083.3(CLCN1):c.1444G>A (p.Gly482Arg)
Variation ID: 546108 Accession: VCV000546108.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q34 7: 143339295 (GRCh38) [ NCBI UCSC ] 7: 143036388 (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 4, 2013 May 12, 2024 Mar 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000083.3:c.1444G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000074.3:p.Gly482Arg missense NR_046453.2:n.1399G>A non-coding transcript variant NC_000007.14:g.143339295G>A NC_000007.13:g.143036388G>A NG_009815.2:g.28170G>A - Protein change
- G482R
- Other names
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- Canonical SPDI
- NC_000007.14:143339294:G:A
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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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CLCN1 | - | - |
GRCh38 GRCh37 |
1369 | 1517 |
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
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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 (2) |
criteria provided, single submitter
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Nov 5, 2023 | RCV000019088.27 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2022 | RCV000657922.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV000810078.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 25, 2024 | RCV003989574.1 |
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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Likely pathogenic
(May 03, 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: SCV000779689.2
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
Comment:
Observed in the heterozygous state, without a second pathogenic variant, in multiple individuals with Thomson disease (domiant form), although some individuals were reported to have … (more)
Observed in the heterozygous state, without a second pathogenic variant, in multiple individuals with Thomson disease (domiant form), although some individuals were reported to have clinical features consistent with the more severe Becker disease (recessive form) (Meyer-Kleine et al., 1995; Jou et al., 2004; Lo Monaco et al., 2004); Observed in the heterozygous state in a patient with myotonia congenita and was found to be inherited from an unaffected father (Jou et al., 2004); Observed in patients with myotonia congenita who harbored a second CLCN1 variant in the literature and referred for genetic testing at GeneDx (Lo Monaco et al., 2015); Published functional studies with electrophysiological analysis of Xenopus oocytes demonstrate G482R results in loss of CLCN1 channel function (Lin et al., 2006); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23739125, 17097617, 10644771, 15311340, 24349310, 25065301, 28427807, 15786415, 12210360, 8533761, 31567646, 31544778, 22346025) (less)
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Pathogenic
(Feb 29, 2020)
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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: SCV002019320.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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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
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Invitae
Accession: SCV000950265.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 482 of the CLCN1 protein (p.Gly482Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 482 of the CLCN1 protein (p.Gly482Arg). This variant is present in population databases (rs746125212, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 22346025, 25065301; Invitae). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal dominant myotonia congenita (PMID: 8533761, 15311340, 15786415, 31567646); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 546108). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLCN1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 10644771, 17097617, 18035046). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Congenital myotonia, autosomal dominant form
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806106.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Nov 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital myotonia, autosomal recessive form
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812289.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in CLCN1 is predicted to replace glycine with arginine at codon 482, p.(Gly482Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in CLCN1 is predicted to replace glycine with arginine at codon 482, p.(Gly482Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is a critical glycine residue in the helical transmembrane M-N Linker domain of the chloride ion channel (PMID: 24349310). There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.01% (2/16,256 alleles) in the African/African American population, which is consistent with a recessive disease. This variant has been detected in at least three individuals with autosomal recessive/Becker myotonia congenita (MC). Of those individuals, one individual was homozygous and two were compound heterozygous for the variant and a pathogenic variant, confirmed in trans (PMID: 22346025, 37066920; LOVD). The variant is reported to segregate with disease in the homozygous state in a single family (PMID: 22346025). There are limited reports of the variant in autosomal dominant/Thomsen MC (PMID: 15311340, 31567646). In vitro patch-clamp assays with limited validation in HEK293 cells and Xenopus oocytes demonstrate the variant leads to a loss of chloride channel function (PMID: 10644771, 17097617, 18035046). Computational evidence [predicts a deleterious effect/ predicts a benign effect/ is uninformative] for the missense substitution (REVEL = 0.997). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PM1, PP3_Moderate, PM2_Supporting, PS3_Supporting, PP1. (less)
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Pathogenic
(Nov 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004161241.5
First in ClinVar: Nov 20, 2023 Last updated: May 12, 2024 |
Comment:
CLCN1: PS3, PS4, PM2, PM5, PP3, PS2:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Oct 07, 2013)
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no assertion criteria provided
Method: literature only
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MYOTONIA CONGENITA, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039376.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected members of a family with Becker myotonia congenita (255700), Koch et al. (1994) identified a mutation in the CLCN1 gene, resulting in a … (more)
In affected members of a family with Becker myotonia congenita (255700), Koch et al. (1994) identified a mutation in the CLCN1 gene, resulting in a gly482-to-arg (G482R) substitution. Interestingly, this mutation producing a recessive phenotype is only 2 codons removed from a pro480-to-leu (P480L; 118425.0006) mutation which results in the dominant Thomsen type of myotonia congenita. (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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Diagnostic Challenges of Neuromuscular Disorders after Whole Exome Sequencing. | Chen PS | Journal of neuromuscular diseases | 2023 | PMID: 37066920 |
Electromyographic Features in a Chinese Cohort With Hereditary Skeletal Muscle Channelopathies. | Sun J | Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society | 2020 | PMID: 31567646 |
Effect of mexiletine on transitory depression of compound motor action potential in recessive myotonia congenita. | Lo Monaco M | Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology | 2015 | PMID: 25065301 |
CLCN1 mutations in Czech patients with myotonia congenita, in silico analysis of novel and known mutations in the human dimeric skeletal muscle chloride channel. | Skálová D | PloS one | 2013 | PMID: 24349310 |
Moroccan consanguineous family with Becker myotonia and review. | Ratbi I | Annals of Indian Academy of Neurology | 2011 | PMID: 22346025 |
Functional studies of the effect of NO donor on human CLCN1 polymorphism/mutants expressed in Xenopus laevis oocytes. | Lin MJ | Biochemical and biophysical research communications | 2008 | PMID: 18035046 |
Functional characterization of CLCN1 mutations in Taiwanese patients with myotonia congenita via heterologous expression. | Lin MJ | Biochemical and biophysical research communications | 2006 | PMID: 17097617 |
Phenotypic variability in myotonia congenita. | Colding-Jørgensen E | Muscle & nerve | 2005 | PMID: 15786415 |
Novel CLCN1 mutations in Taiwanese patients with myotonia congenita. | Jou SB | Journal of neurology | 2004 | PMID: 15311340 |
Mechanism of inverted activation of ClC-1 channels caused by a novel myotonia congenita mutation. | Zhang J | The Journal of biological chemistry | 2000 | PMID: 10644771 |
Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia. | Meyer-Kleine C | American journal of human genetics | 1995 | PMID: 8533761 |
Koch, M. C., Meyer-Kleine, C., Otto, M., Ricker, K., Lorenz, C., Steinmeyer, K., Jentsch, T. J. Mutations in the CLCN1 gene leading to myotonia congenita Thomsen and generalized myotonia Becker. (Abstract) Am. J. Hum. Genet. 55 (suppl.): A226, 1994. | - | - | - | - |
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Text-mined citations for rs746125212 ...
HelpRecord last updated May 12, 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.