NM_000083.3(CLCN1):c.1453A>G (p.Met485Val) AND Congenital myotonia, autosomal recessive form

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Nov 5, 2023
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:: RCV001589311.5

Allele description [Variation Report for NM_000083.3(CLCN1):c.1453A>G (p.Met485Val)]

NM_000083.3(CLCN1):c.1453A>G (p.Met485Val)

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.1453A>G (p.Met485Val)

HGVS:

NC_000007.14:g.143339304A>G
NG_009815.2:g.28179A>G
NM_000083.3:c.1453A>GMANE SELECT
NP_000074.3:p.Met485Val
NC_000007.13:g.143036397A>G
NG_009815.1:g.28179A>G
NM_000083.2:c.1453A>G
NR_046453.2:n.1408A>G
P35523:p.Met485Val

Protein change:

M485V

Links:

UniProtKB: P35523#VAR_001609; dbSNP: rs146457619

NCBI 1000 Genomes Browser:

rs146457619

Molecular consequence:

NM_000083.3:c.1453A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.1408A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Congenital myotonia, autosomal recessive form
Synonyms:: BECKER DISEASE; Myotonia congenita autosomal recessive; 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
SCV001815688	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Sep 23, 2020)	inherited	clinical testing	Citation Link,
SCV002760031	GenomeConnect - Brain Gene Registry	no classification provided	not provided	maternal	phenotyping only
SCV004099583	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 7, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8533761, 34529042, 9158157 Citation Link,
SCV004812552	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 5, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8533761, 9158157, 22094069, 24349310, 24920213, 31544778, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only
not provided	inherited	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Translating genetic and functional data into clinical practice: a series of 223 families with myotonia.

Suetterlin K, Matthews E, Sud R, McCall S, Fialho D, Burge J, Jayaseelan D, Haworth A, Sweeney MG, Kullmann DM, Schorge S, Hanna MG, Männikkö R.

Brain. 2022 Apr 18;145(2):607-620. doi: 10.1093/brain/awab344.

PubMed [citation]

PMID:: 34529042
PMCID:: PMC9014745

Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia.

Meyer-Kleine C, Steinmeyer K, Ricker K, Jentsch TJ, Koch MC.

Am J Hum Genet. 1995 Dec;57(6):1325-34.

PubMed [citation]

PMID:: 8533761
PMCID:: PMC1801423

See all PubMed Citations (8)

Details of each submission

From New York Genome Center - CSER-NYCKidSeq, SCV001815688.1

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

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

From GenomeConnect - Brain Gene Registry, SCV002760031.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Pathogenic and reported on 09-23-2020 by Lab or GTR ID New York Genome Center. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	unknown	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, SCV004099583.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: CLCN1 c.1453A>G (p.Met485Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 251490 control chromosomes (gnomAD). c.1453A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with autosomal recessive Congenital Myotonia, including at least one case where it was confirmed to be in trans with a pathogenic variant and was found to segregate with the disease phenotype within members of the same family (e.g. Meyer-Kleine_1995, Suetterlin_2022). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating the variant in Xenopus oocytes and found that the variant severely impairs channel function, but does not exert a dominant negative effect when expressed with the wild type protein, consistent with it having an autosomal recessive mode of inheritance (e.g. Wollnik_1997, Suetterlin_2022). The following publications have been ascertained in the context of this evaluation (PMID: 8533761, 34529042, 9158157). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The majority of submitters classified the variant as pathogenic (n=6) and others classified it as uncertain significance (n=2). 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 Molecular Genetics, Royal Melbourne Hospital, SCV004812552.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change in CLCN1 is predicted to replace methionine with valine at codon 485, p.(Met485Val). The methionine residue is highly conserved (100 vertebrates, UCSC), and is a critical methionine residue in the helical transmembrane M-N Linker domain of the chloride ion channel (PMID: 24349310). There is a small physicochemical difference between methionine and valine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.06% (84/129,188 alleles) in the European (non-Finnish) population. This variant has been detected in multiple individuals with autosomal recessive/Becker myotonia congenita in the homozygous and compound heterozygous state and segregates with recessive disease in at least one family (PMID: 8533761, 24920213, 31544778, 22094069). An in vitro patch-clamp assay with limited validation in Xenopus oocytes demonstrates the variant causes a loss of chloride channel function and no dominant negative effect (PMID: 9158157). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.774). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM1, PP1, PP3, PS3_Supporting.

#	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

Last Updated: Jan 13, 2025

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