NM_000083.3(CLCN1):c.2680C>T (p.Arg894Ter) AND Congenital myotonia, autosomal recessive form

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jun 18, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000019098.41

Allele description [Variation Report for NM_000083.3(CLCN1):c.2680C>T (p.Arg894Ter)]

NM_000083.3(CLCN1):c.2680C>T (p.Arg894Ter)

Gene:

CLCN1:chloride voltage-gated channel 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q34

Genomic location:

Preferred name:

NM_000083.3(CLCN1):c.2680C>T (p.Arg894Ter)

HGVS:

NC_000007.14:g.143351678C>T
NG_009815.2:g.40553C>T
NM_000083.3:c.2680C>TMANE SELECT
NP_000074.3:p.Arg894Ter
NC_000007.13:g.143048771C>T
NG_009815.1:g.40553C>T
NM_000083.2:c.2680C>T
NR_046453.2:n.2635C>T
p.Arg894*
p.Arg894X

Protein change:

R894*; ARG894TER

Links:

OMIM: 118425.0015; dbSNP: rs55960271

NCBI 1000 Genomes Browser:

rs55960271

Molecular consequence:

NR_046453.2:n.2635C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000083.3:c.2680C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Congenital myotonia, autosomal recessive form
Synonyms:: Myotonia congenita autosomal recessive; Becker disease; Myotonia generalized; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009715; MedGen: C0751360; Orphanet: 614; OMIM: 255700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000039386	OMIM	no assertion criteria provided	Pathogenic (May 1, 2009)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 11933197, 8533761, 11840191, 18337100
SCV001367211	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 28, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001976940	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 1, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34008892, 25741868
SCV002555960	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 17, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8533761, 17990293, 23152584, 24349310 Citation Link,
SCV004100819	Neurogenomics Lab, Neuroscience Institute, University Of Cape Town - International Center for Genomic Medicine for Neuromuscular Disease (ICGNMD).	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2024)	germline	research	PubMed (2) [See all records that cite these PMIDs] 37712079, 25741868
SCV004171140	Institute of Human Genetics, University Hospital of Duesseldorf	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	not provided	PubMed (1) [See all records that cite this PMID]
SCV004812152	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 18, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	1	not provided	not provided	not provided	research, not provided
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Myotonia caused by mutations in the muscle chloride channel gene CLCN1.

Pusch M.

Hum Mutat. 2002 Apr;19(4):423-34. Review.

PubMed [citation]

PMID:: 11933197

Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia.

Sun C, Tranebjaerg L, Torbergsen T, Holmgren G, Van Ghelue M.

Eur J Hum Genet. 2001 Dec;9(12):903-9. Erratum in: Eur J Hum Genet. 2010 Feb;18(2):264.

PubMed [citation]

PMID:: 11840191

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000039386.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

Description

For discussion of the arg894-to-ter (R894X) mutation in the CLCN1 gene that was found in compound heterozygous state in sibs with autosomal recessive myotonia congenita (255700) by Pusch et al. (1995), see 118425.0010.

In patients with both autosomal recessive and autosomal dominant (160800) myotonia congenita, Meyer-Kleine et al. (1995) identified a mutation in the CLCN1 gene, resulting in an R894X substitution. Functional expression of the R894X mutant in Xenopus oocytes revealed a large reduction, but not complete abolition, of chloride currents. Further, it had a weak dominant-negative effect on wildtype currents in coexpression studies. Reduction of currents predicted for heterozygous carriers were close to the borderline value, sufficient to elicit myotonia.

Sun et al. (2001) found a carrier frequency of 0.87% for the R894X mutation in the northern Scandinavian population.

In a French Canadian family with myotonia, Dupre et al. (2009) found that the R894X mutation could be expressed in a semidominant or recessive manner. The proband, who was heterozygous for the R894X mutation, had muscle stiffness and mild warm-up phenomenon, but no significant percussion myotonia and no myotonia on EMG. In contrast, her daughters, who were compound heterozygous for the R894X and R300X (118425.0017) mutations, showed a moderately severe phenotype with generalized hypertrophy consistent with autosomal recessive Becker myotonia. This compound heterozygous genotype showed resistance to phenytoin, mexiletine, and quinine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001367211.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM3_STR.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV001976940.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

PVS1, PP3, PP4, PP5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002555960.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: CLCN1 c.2680C>T (p.Arg894X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with myotonia congenita in HGMD. c.2680C>T has been reported in the literature in multiple homozygous, compound heterozygous and heterozygous individuals affected with Congenital Myotonia (Raheem_2012 and Skalova_2013). Individuals who were homozygous for this variant had reduced sarcolemmal ClC-1 expression (Raheem_2012). Functional studies in Xenopus oocytes demonstrated that the variant resulted in greatly reduced chloride currents compared to wild type (Meyer-Kleine_1995). Papponen_2008 have demonstrated that this variant did not inhibit transport of the protein but did cause reduced stability in myotubes. These data indicate that the variant is very likely to be associated with disease. Eighteen submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS(n=1), likely pathogenic(n=4) and pathogenic (n=13). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neurogenomics Lab, Neuroscience Institute, University Of Cape Town - International Center for Genomic Medicine for Neuromuscular Disease (ICGNMD)., SCV004100819.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)

Description

Proband also has heterozygous pathogenic CLCN1 p.Pro480HisfsTer24 frameshift variant (not confirmed in trans).

Description

PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.01660 (1.6%; 417/25122 alleles in European Finnish population, including 5 homozygous observations) and gnomAD v3.1.2 is 0.01564 (1.6%; 166/10612 alleles in European Finnish population, including 1 homozygous observation). The heterozygous carrier frequency in gnomAD is calculated to be 0.032, i.e. 1 in 31 individuals in Finnish European population). This carrier frequency is not inconsistent with the reported high frequency of AR myotonia congenital in Scandinavia viz. 7.3 per 100 000 in Northern Finland (PMID 9598722) and 9.4 per 100 000 in Northern Norway (PMID 11840191). PVS1_moderate: nonsense variant not predicted to undergo NMD (occurs in 3' most exon 23). Role of exon 23 in protein function is unknown. At least 3 other pathogenic LOF variants in exon 23 have been identified in patients with AR myotonia congenita. This variant removes <10% of the protein. PM3_verystrong: this variant has been found in a compound heterozygous state in multiple individuals with AR myotonia congenital (>4 points). PS4 met: this variant has been described in more than 10 unrelated probands with autosomal recessive myotonia congenita (both homozygous and compound heterozygous observations) (PMID 11184019). PS3 supporting: functional studies provide supportive evidence that the variant has a damaging effect on the gene or gene product. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	1	not provided

From Institute of Human Genetics, University Hospital of Duesseldorf, SCV004171140.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004812152.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Criteria applied: PM3_VSTR,PVS1_MOD,PS3_MOD

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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