ClinVar Genomic variation as it relates to human health
NM_000083.3(CLCN1):c.950G>A (p.Arg317Gln)
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.950G>A (p.Arg317Gln)
Variation ID: 17542 Accession: VCV000017542.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q34 7: 143330868 (GRCh38) [ NCBI UCSC ] 7: 143027961 (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 Jun 9, 2024 Feb 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000083.3:c.950G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000074.3:p.Arg317Gln missense NR_046453.2:n.1055G>A non-coding transcript variant NC_000007.14:g.143330868G>A NC_000007.13:g.143027961G>A NG_009815.2:g.19743G>A P35523:p.Arg317Gln - Protein change
- R317Q
- Other names
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- Canonical SPDI
- NC_000007.14:143330867: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 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 |
1375 | 1523 |
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
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
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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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 7, 2024 | RCV000019094.31 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 7, 2024 | RCV000019095.31 | |
not provided (1) |
no classification provided
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- | RCV000020121.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2023 | RCV000516960.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2017 | RCV000626585.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 3, 2023 | RCV000763169.9 |
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
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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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Pathogenic
(Nov 04, 2016)
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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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Athena Diagnostics
Accession: SCV000612809.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Likely pathogenic
(Jan 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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EMG: myotonic runs
EMG: neuropathic changes Limb pain Memory impairment Migraine Muscle spasm
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747286.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Congenital myotonia, autosomal dominant form
Congenital myotonia, autosomal recessive form
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893758.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Aug 26, 2019)
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criteria provided, single submitter
Method: research
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Congenital myotonia, autosomal dominant form
Affected status: yes
Allele origin:
maternal
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI WGS
Accession: SCV001190886.1 First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Attention deficit hyperactivity disorder (present) , Autistic behavior (present)
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Likely pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Congenital myotonia, autosomal recessive form
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369057.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP3,PP2.
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Pathogenic
(Sep 01, 2023)
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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: SCV002044125.3
First in ClinVar: Jan 01, 2022 Last updated: Sep 14, 2023 |
Comment:
Reported in the heterozygous state in several families, but also in the heterozygous and homozygous state in one family with myotonia congenita (Meyer-Kleine et al., … (more)
Reported in the heterozygous state in several families, but also in the heterozygous and homozygous state in one family with myotonia congenita (Meyer-Kleine et al., 1995; Esteban et al., 1998), and not observed in homozygous state in controls; Published functional studies indicate that R317Q shifts the gating threshold to a positive voltage thus altering channel gating and preventing repolarization of the channel (Pusch et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); 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: 24349310, 25749817, 17395130, 12163078, 11933197, 15786415, 27415035, 9736777, 10737121, 8533761, 8845168, 34529042, 35907044) (less)
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Pathogenic
(Sep 03, 2023)
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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: SCV000931840.6
First in ClinVar: Aug 13, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 317 of the CLCN1 protein (p.Arg317Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 317 of the CLCN1 protein (p.Arg317Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant and recessive myotonia congenita (PMID: 8533761, 10737121, 29606556; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17542). For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 8845168). (less)
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Pathogenic
(Feb 07, 2024)
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criteria provided, single submitter
Method: clinical testing
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Congenital myotonia, autosomal recessive form
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005049691.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
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Pathogenic
(Feb 07, 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:
unknown
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Baylor Genetics
Accession: SCV005049859.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
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Pathogenic
(Mar 01, 1998)
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no assertion criteria provided
Method: literature only
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MYOTONIA CONGENITA, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039383.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 15, 2016 |
Comment on evidence:
The arg317-to-gln (R317Q) mutation illustrates the resultant occurrence of either autosomal dominant myotonia congenita (160800) or autosomal recessive myotonia congenita (255700), depending on the family … (more)
The arg317-to-gln (R317Q) mutation illustrates the resultant occurrence of either autosomal dominant myotonia congenita (160800) or autosomal recessive myotonia congenita (255700), depending on the family background. Meyer-Kleine et al. (1995) observed the R317Q mutation in dominant Thomsen myotonia congenita; Esteban et al. (1998) observed it in Becker myotonia congenita and pointed to other mutations that had been observed as a recessive or a dominant, depending on the particular family. (less)
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Pathogenic
(Mar 01, 1998)
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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: SCV000039382.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 15, 2016 |
Comment on evidence:
The arg317-to-gln (R317Q) mutation illustrates the resultant occurrence of either autosomal dominant myotonia congenita (160800) or autosomal recessive myotonia congenita (255700), depending on the family … (more)
The arg317-to-gln (R317Q) mutation illustrates the resultant occurrence of either autosomal dominant myotonia congenita (160800) or autosomal recessive myotonia congenita (255700), depending on the family background. Meyer-Kleine et al. (1995) observed the R317Q mutation in dominant Thomsen myotonia congenita; Esteban et al. (1998) observed it in Becker myotonia congenita and pointed to other mutations that had been observed as a recessive or a dominant, depending on the particular family. (less)
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Pathogenic
(Apr 06, 2022)
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no assertion criteria provided
Method: research
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Congenital myotonia, autosomal dominant form
Affected status: yes
Allele origin:
germline
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Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences
Accession: SCV002549792.1
First in ClinVar: Jul 23, 2022 Last updated: Jul 23, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Batten-Turner congenital myopathy
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000040441.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Congenital myotonia, autosomal dominant form
Congenital myotonia, autosomal recessive 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:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228549.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Pathogenic and reported on 05-01-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 05-01-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormality of eye movement (present) , Abnormality of vision (present) , Myopia (present) , Hypercholesterolemia (present) , Decreased pulmonary function (present) , Respiratory insufficiency (present) … (more)
Abnormality of eye movement (present) , Abnormality of vision (present) , Myopia (present) , Hypercholesterolemia (present) , Decreased pulmonary function (present) , Respiratory insufficiency (present) , Abnormal pattern of respiration (present) , Abnormal erythrocyte morphology (present) , Abnormality of the liver (present) , Abnormal stomach morphology (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Type 2 diabetes mellitus (present) , Anxiety (present) , Depression (present) (less)
Indication for testing: Diagnostic
Age: 40-49 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-05-01
Testing laboratory interpretation: Pathogenic
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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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Myotonia Congenita. | Adam MP | - | 2021 | PMID: 20301529 |
Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands. | Stunnenberg BC | Neuromuscular disorders : NMD | 2018 | PMID: 29606556 |
The Overlap between Fibromyalgia Syndrome and Myotonia Congenita. | Nam TS | Journal of clinical neurology (Seoul, Korea) | 2015 | PMID: 25749817 |
CLC chloride channels: correlating structure with function. | Estévez R | Current opinion in structural biology | 2002 | PMID: 12163078 |
Identification of two mutations and a polymorphism in the chloride channel CLCN-1 in patients with Becker's generalized myotonia. | Esteban J | Neurogenetics | 1998 | PMID: 10737121 |
Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the CIC-1 chloride channel. | Pusch M | Neuron | 1995 | PMID: 8845168 |
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 |
Text-mined citations for rs80356702 ...
HelpRecord last updated Jun 17, 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.