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NM_000083.3(CLCN1):c.803C>T (p.Thr268Met)

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Interpretation:
Pathogenic/Likely pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
5 (Most recent: Jan 7, 2021)
Last evaluated:
Feb 24, 2020
Accession:
VCV000021047.2
Variation ID:
21047
Description:
single nucleotide variant
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NM_000083.3(CLCN1):c.803C>T (p.Thr268Met)

Allele ID
33899
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
7q34
Genomic location
7: 143324442 (GRCh38) GRCh38 UCSC
7: 143021535 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000007.13:g.143021535C>T
NC_000007.14:g.143324442C>T
NM_000083.3:c.803C>T MANE Select NP_000074.3:p.Thr268Met missense
... more HGVS
Protein change
T268M
Other names
-
Canonical SPDI
NC_000007.14:143324441:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00001
Links
ClinGen: CA341551
dbSNP: rs80356687
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic/Likely pathogenic 2 criteria provided, multiple submitters, no conflicts Mar 23, 2016 RCV000497783.2
Pathogenic 2 criteria provided, multiple submitters, no conflicts Feb 24, 2020 RCV000763168.2
Pathogenic 1 no assertion criteria provided Apr 12, 2011 RCV000020114.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
CLCN1 - - GRCh38
GRCh37
621 666

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Congenital myotonia, autosomal dominant form
Congenital myotonia, autosomal recessive form
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000893756.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Pathogenic
(Feb 24, 2020)
criteria provided, single submitter
Method: clinical testing
Congenital myotonia, autosomal recessive form
Congenital myotonia, autosomal dominant form
Allele origin: germline
Invitae
Accession: SCV001584111.1
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (7)
Comment:
This sequence change replaces threonine with methionine at codon 268 of the CLCN1 protein (p.Thr268Met). The threonine residue is moderately conserved and there is a … (more)
Likely pathogenic
(Mar 02, 2016)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000589658.2
Submitted: (Nov 28, 2017)
Evidence details
Comment:
The T268M variant in the CLCN1 gene has been reported previously as a heterozygous variant along with another frameshift variant (phase unknown) in a patient … (more)
Pathogenic
(Mar 23, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Athena Diagnostics Inc
Accession: SCV000612797.2
Submitted: (Aug 31, 2018)
Evidence details
Publications
PubMed (6)
pathologic
(Apr 12, 2011)
no assertion criteria provided
Method: curation
Myotonia Congenita
Allele origin: not provided
GeneReviews
Accession: SCV000040434.1
Submitted: (Jan 08, 2013)
Evidence details
Comment:
Converted during submission to Pathogenic.

Functional evidence

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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 this variant

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Title Author Journal Year Link
Myotonia Congenita Dunø M - 2021 PMID: 20301529
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia. Furby A Neuromuscular disorders : NMD 2014 PMID: 25088311
Coexistence of DMPK gene expansion and CLCN1 missense mutation in the same patient. Kassardjian CD Neurogenetics 2014 PMID: 24705798
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
[The spectrum of CLCN1 gene mutations in patients with nondystrophic Thomsen's and Becker's myotonias]. Ivanova EA Genetika 2012 PMID: 23113340
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
Comparative efficacy of repetitive nerve stimulation, exercise, and cold in differentiating myotonic disorders. Michel P Muscle & nerve 2007 PMID: 17654559
Involvement of helices at the dimer interface in ClC-1 common gating. Duffield M The Journal of general physiology 2003 PMID: 12566541
Identification of three novel mutations in the major human skeletal muscle chloride channel gene (CLCN1), causing myotonia congenita. Brugnoni R Human mutation 1999 PMID: 10533075
Transient weakness and compound muscle action potential decrement in myotonia congenita. Deymeer F Muscle & nerve 1998 PMID: 9736066

Text-mined citations for rs80356687...

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These 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 May 13, 2021