ClinVar Genomic variation as it relates to human health
NM_000083.3(CLCN1):c.568_569delinsTC (p.Gly190Ser)
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.
Pathogenic(8); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000083.3(CLCN1):c.568_569delinsTC (p.Gly190Ser)
Variation ID: 209139 Accession: VCV000209139.34
- Type and length
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Indel, 2 bp
- Location
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Cytogenetic: 7q34 7: 143321720-143321721 (GRCh38) [ NCBI UCSC ] 7: 143018813-143018814 (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 Sep 29, 2015 May 12, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000083.3:c.568_569delinsTC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000074.3:p.Gly190Ser missense NR_046453.2:n.670_671delinsTC non-coding transcript variant NC_000007.14:g.143321720_143321721delinsTC NC_000007.13:g.143018813_143018814delinsTC NG_009815.2:g.10595_10596delinsTC - Protein change
- G190S
- Other names
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- Canonical SPDI
- NC_000007.14:143321719:GG:TC
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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.
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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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 26, 2024 | RCV000191069.3 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Aug 17, 2023 | RCV000489144.28 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 5, 2023 | RCV000530150.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2017 | RCV000626583.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 27, 2021 | RCV002288796.3 |
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
(Nov 26, 2013)
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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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Baylor Genetics
Study: Adult_WES
Accession: SCV000245461.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Comment:
Likely pathogenicity based on finding it once in our laboratory with a known pathogenic missense variant (F167L; phase unknown) in a 46-year-old male with heart … (more)
Likely pathogenicity based on finding it once in our laboratory with a known pathogenic missense variant (F167L; phase unknown) in a 46-year-old male with heart arrhythmia, hypertrophic cardiomyopathy, neuromuscular disease, EMG evidence of myopathy with myotonic discharges and mild length-dependent neuropathy, poor balance, short stature, scoliosis, small hands. (less)
Number of individuals with the variant: 1
Age: 40-49 years
Sex: male
Ethnicity/Population group: Causasians
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Uncertain significance
(Jan 13, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000704674.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jan 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000612791.4
First in ClinVar: May 22, 2017 Last updated: Dec 31, 2022 |
Comment:
This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls and therefore is consistent with pathogenicity (http://gnomad.broadinstitute.org). This … (more)
This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls and therefore is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been reported in multiple families with autosomal recessive myotonia congenita (PMID: 19697366, 21221019, 22921319, 23113340), however, it has also been reported in individuals with autosomal dominant myotonia congenita (PMID: 23113340, 19697366, 22921319). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to impair channel function by reducing permeability, current density and affecting channel deactivation properties (PMID: 22521272, 23933576). (less)
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Pathogenic
(Jul 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002563982.11
First in ClinVar: Aug 23, 2022 Last updated: May 12, 2024 |
Number of individuals with the variant: 3
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Pathogenic
(Jan 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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EMG: myotonic discharges
Headache Myocardial infarction Myotonia of the upper limb Rigidity Vertigo
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747284.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
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Pathogenic
(Sep 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Congenital myotonia, autosomal dominant form
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580350.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4_MOD, PM3, PM2_SUP, PP1
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Dec 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: SCV000577243.6
First in ClinVar: May 22, 2017 Last updated: Mar 04, 2023 |
Comment:
Published electrophysiological studies in HEK293 cells showed a dramatic positive shift in voltage-dependent activation and highly reduced chloride currents (Desaphy et al., 2013); Not observed … (more)
Published electrophysiological studies in HEK293 cells showed a dramatic positive shift in voltage-dependent activation and highly reduced chloride currents (Desaphy et al., 2013); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26633545, 23739125, 32117024, 32664137, 23933576, 22921319, 23113340, 24349310, 19697366, 22521272, 29606556, 32558419, 33013670, 32655465, 29809153) (less)
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Pathogenic
(Aug 17, 2023)
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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: SCV002017368.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 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
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: SCV000649786.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 190 of the CLCN1 protein (p.Gly190Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 190 of the CLCN1 protein (p.Gly190Ser). This variant is present in population databases (rs797045032, gnomAD 0.004%). This missense change has been observed in individuals with autosomal dominant and autosomal recessive myotonia congenita (PMID: 19697366, 21221019, 22521272, 22921319, 23739125, 24349310, 26007199). It has also been observed to segregate with disease in related individuals; in the heterozygous state this variant was reported to be incompletely penetrant and in the homozygous state it was reported to cause a more severe phenotype (PMID: 19697366, 22921319). ClinVar contains an entry for this variant (Variation ID: 209139). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 22521272, 23933576). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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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. (Autosomal unknown)
Affected status: yes
Allele origin:
germline
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Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences
Accession: SCV005038736.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Comment:
The c.568_569delinsTC (p.(Gly190Ser)) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita. No other Pathogenic or Likely pathogenic variants were … (more)
The c.568_569delinsTC (p.(Gly190Ser)) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita. No other Pathogenic or Likely pathogenic variants were found in this individual. According to PMID: 26007199, this variant is found in the highly conserved ClC-1 helix D motif, which plays a critical role in the chloride ion pathway. This variant has been reported in multiple families with autosomal recessive myotonia congenita (PMID: 19697366, 21221019, 22921319, 23113340), however, it has also been reported in individuals with autosomal dominant myotonia congenita (PMID: 23113340, 19697366, 22921319). As shown in PMID: 23933576, this variant in the heterozygous state manifests as asymptomatic or with only mild manifestations. (less)
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Mar 26, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005039085.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Comment:
Variant summary: CLCN1 c.568_569delinsTC (p.Gly190Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging … (more)
Variant summary: CLCN1 c.568_569delinsTC (p.Gly190Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251480 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CLCN1 causing Congenital Myotonia, Autosomal Recessive Form (4.4e-05 vs ND), allowing no conclusion about variant significance. c.568_569delinsTC has been reported in the literature in multiple individuals affected with Congenital Myotonia, Autosomal Recessive Form. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. ClinVar contains an entry for this variant (Variation ID: 209139). Based on the evidence outlined above, the variant was classified as pathogenic. (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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Pathomechanisms of a CLCN1 Mutation Found in a Russian Family Suffering From Becker's Myotonia. | Altamura C | Frontiers in neurology | 2020 | PMID: 33013670 |
Congenital myotonia: a review of twenty cases and a new splice-site mutation in the CLCN1 gene. | Özgün N | The Turkish journal of pediatrics | 2020 | PMID: 32558419 |
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 |
Molecular diagnostic experience of whole-exome sequencing in adult patients. | Posey JE | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26633545 |
Clinical, Molecular, and Functional Characterization of CLCN1 Mutations in Three Families with Recessive Myotonia Congenita. | Portaro S | Neuromolecular medicine | 2015 | PMID: 26007199 |
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 |
Functional characterization of ClC-1 mutations from patients affected by recessive myotonia congenita presenting with different clinical phenotypes. | Desaphy JF | Experimental neurology | 2013 | PMID: 23933576 |
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 |
Stiffness as a presenting symptom of an odd clinical condition caused by multiple sclerosis and myotonia congenita. | Portaro S | Neuromuscular disorders : NMD | 2013 | PMID: 22921319 |
[The spectrum of CLCN1 gene mutations in patients with nondystrophic Thomsen's and Becker's myotonias]. | Ivanova EA | Genetika | 2012 | PMID: 23113340 |
Myotonia congenita: novel mutations in CLCN1 gene and functional characterizations in Italian patients. | Ulzi G | Journal of the neurological sciences | 2012 | PMID: 22521272 |
Low-rate repetitive nerve stimulation protocol in an Italian cohort of patients affected by recessive myotonia congenita. | Modoni A | Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society | 2011 | PMID: 21221019 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CLCN1 | - | - | - | - |
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Text-mined citations for rs797045032 ...
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.