ClinVar Genomic variation as it relates to human health
NM_000083.3(CLCN1):c.920T>C (p.Phe307Ser)
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.920T>C (p.Phe307Ser)
Variation ID: 21050 Accession: VCV000021050.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q34 7: 143330838 (GRCh38) [ NCBI UCSC ] 7: 143027931 (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 Mar 16, 2024 Nov 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000083.3:c.920T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000074.3:p.Phe307Ser missense NR_046453.2:n.1025T>C non-coding transcript variant NC_000007.14:g.143330838T>C NC_000007.13:g.143027931T>C NG_009815.2:g.19713T>C P35523:p.Phe307Ser - Protein change
- F307S
- Other names
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- Canonical SPDI
- NC_000007.14:143330837:T:C
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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) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Exome Aggregation Consortium (ExAC) 0.00009
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 |
1361 | 1508 |
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 (1) |
criteria provided, single submitter
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Nov 18, 2018 | RCV000020118.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 26, 2022 | RCV000483128.11 | |
Pathogenic (2) |
criteria provided, single submitter
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Nov 25, 2023 | RCV000477848.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 20, 2022 | RCV002243656.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 7, 2023 | RCV003964807.1 |
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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Pathogenic
(Nov 18, 2018)
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criteria provided, single submitter
Method: clinical testing
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Myotonia congenita
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915213.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The CLCN1 c.920T>C (p.Phe307Ser) variant is a missense variant that has been reported in at least 12 unrelated individuals with myotonia congenita (Kubisch et al. … (more)
The CLCN1 c.920T>C (p.Phe307Ser) variant is a missense variant that has been reported in at least 12 unrelated individuals with myotonia congenita (Kubisch et al. 1998; Sun et al. 2001; Colding-Jorgensen et al. 2003; Fialho et al. 2007; Raheem et al. 2012; Horga et al. 2013). In the majority of cases, the variant acted in an autosomal dominant manner, but several of cases of compound heterozygosity and autosomal recessive inheritance were also reported. The p.Phe307Ser variant was absent from 50 controls but is reported at a frequency of 0.000155 in the European (Finnish) population of the Genome Aggregation Database. Functional studies in Xenopus oocytes showed a shifted voltage dependence of the variant channel that was expected to prevent efficient repolarization of the muscle action potential, a finding that has been seen with other disease-causing variants. (Kubisch et al. 1998; Aromataris et al. 2001). Based on the collective evidence, the p.Phe307Ser variant is classified as pathogenic for myotonia congenita. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Apr 20, 2022)
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criteria provided, single submitter
Method: research
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Congenital myotonia, autosomal dominant form
Affected status: yes
Allele origin:
paternal
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: HudsonAlpha-AGHI-WGS
Accession: SCV002515840.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG codes: PS4_Moderate, PS3, PM2, PP3
Number of individuals with the variant: 1
Clinical Features:
Macrocephaly (present) , Delayed speech and language development (present) , Global developmental delay (present) , Large for gestational age (present) , Complex febrile seizure (present)
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Pathogenic
(Sep 26, 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 Inc
Accession: SCV000612804.4
First in ClinVar: Apr 27, 2017 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been reported in multiple individuals with myotonia congenita … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been reported in multiple individuals with myotonia congenita together with a single recessive pathogenic variant in the same gene (PMID: 17932099, 12661046, 35350395), however, it has also been reported in individuals with possible autosomal dominant myotonia congenita (PMID: 11840191, 23516313, 23152584). Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 11408615, 9736777. (less)
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Pathogenic
(Oct 10, 2019)
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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: SCV002019318.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 25, 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: SCV000759738.8
First in ClinVar: Apr 23, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 307 of the CLCN1 protein (p.Phe307Ser). … (more)
This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 307 of the CLCN1 protein (p.Phe307Ser). This variant is present in population databases (rs80356701, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 9736777, 17932099, 23152584, 23516313). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 21050). 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: 9736777, 11408615). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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CLCN1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004783743.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The CLCN1 c.920T>C variant is predicted to result in the amino acid substitution p.Phe307Ser. This variant has been reported in multiple unrelated individuals and families … (more)
The CLCN1 c.920T>C variant is predicted to result in the amino acid substitution p.Phe307Ser. This variant has been reported in multiple unrelated individuals and families with myotonia congenita (Kubisch et al. 1998. PubMed ID: 9736777; Sun et al. 2001. PubMed ID: 11840191; Fialho et al. 2007. PubMed ID: 17932099; Raheem et al. 2012. PubMed ID: 23152584; Horga et al. 2013. PubMed ID: 23516313). In most cases, this variant has displayed dominant inheritance but it has also been reported in the homozygous or compound heterozygous state with another pathogenic variant (Fialho et al. 2007. PubMed ID: 17932099; Horga et al. 2013. PubMed ID: 23516313). This variant is reported in 0.012% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-143027931-T-C). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 02, 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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GeneDx
Accession: SCV000567635.6
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Reported in multiple unrelated families with myotonia congenita, in association with both autosomal dominant and autosomal recessive inheritance (Kubisch et al., 1998; Colding-Jorgensen et al., … (more)
Reported in multiple unrelated families with myotonia congenita, in association with both autosomal dominant and autosomal recessive inheritance (Kubisch et al., 1998; Colding-Jorgensen et al., 2003; Fialho et al., 2007; Wang et al., 2022); Published functional studies demonstrate a shift in voltage dependence towards positive potentials, and the altered protein displayed a dominant-negative effect when expressed with wild type protein (Kubisch et al., 1998; Aromataris et al., 2001); Not observed at a 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, 11840191, 11408615, 17932099, 15162127, 12661046, 23152584, 23516313, 32010054, 32906206, 34529042, 35350395, 9736777) (less)
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Likely pathogenic
(May 12, 2016)
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no assertion criteria provided
Method: research
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Congenital myotonia, autosomal dominant form
Congenital myotonia, autosomal recessive form
Affected status: unknown
Allele origin:
maternal
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536752.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
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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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The Clinical, Myopathological, and Genetic Analysis of 20 Patients With Non-dystrophic Myotonia. | Wang Q | Frontiers in neurology | 2022 | PMID: 35350395 |
Molecular determinants of common gating of a ClC chloride channel. | Bennetts B | Nature communications | 2013 | PMID: 24064982 |
Prevalence study of genetically defined skeletal muscle channelopathies in England. | Horga A | Neurology | 2013 | PMID: 23516313 |
New immunohistochemical method for improved myotonia and chloride channel mutation diagnostics. | Raheem O | Neurology | 2012 | PMID: 23152584 |
Chloride channel myotonia: exon 8 hot-spot for dominant-negative interactions. | Fialho D | Brain : a journal of neurology | 2007 | PMID: 17932099 |
Decrement of compound muscle action potential is related to mutation type in myotonia congenita. | Colding-Jørgensen E | Muscle & nerve | 2003 | PMID: 12661046 |
Involvement of helices at the dimer interface in ClC-1 common gating. | Duffield M | The Journal of general physiology | 2003 | PMID: 12566541 |
Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia. | Sun C | European journal of human genetics : EJHG | 2001 | PMID: 11840191 |
Fast and slow gating of CLC-1: differential effects of 2-(4-chlorophenoxy) propionic acid and dominant negative mutations. | Aromataris EC | Molecular pharmacology | 2001 | PMID: 11408615 |
ClC-1 chloride channel mutations in myotonia congenita: variable penetrance of mutations shifting the voltage dependence. | Kubisch C | Human molecular genetics | 1998 | PMID: 9736777 |
Text-mined citations for rs80356701 ...
HelpRecord last updated Mar 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.