VCV000017531.59 - ClinVar

NM_000083.3(CLCN1):c.1238T>G (p.Phe413Cys)

Germline

Classification

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.

(16)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000083.3(CLCN1):c.1238T>G (p.Phe413Cys)

Variation ID: 17531 Accession: VCV000017531.59

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q34 7: 143332490 (GRCh38) [ NCBI UCSC ] 7: 143029583 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Oct 20, 2024	Jul 2, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000083.3:c.1238T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000074.3:p.Phe413Cys	missense
NR_046453.2:n.1343T>G		non-coding transcript variant
NC_000007.14:g.143332490T>G
NC_000007.13:g.143029583T>G
NG_009815.2:g.21365T>G
	P35523:p.Phe413Cys

... more HGVS ... less HGVS

Protein change

F413C

Other names

Canonical SPDI

NC_000007.14:143332489:T:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00011

The Genome Aggregation Database (gnomAD) 0.00028

Exome Aggregation Consortium (ExAC) 0.00032

The Genome Aggregation Database (gnomAD), exomes 0.00037

Links

ClinGen: CA258010 UniProtKB: P35523#VAR_001604 OMIM: 118425.0001 dbSNP: rs121912799 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help 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.
CLCN1		-	-	GRCh38 GRCh37	1400	1552

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help 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 Help 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 Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Congenital myotonia, autosomal recessive form	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 2, 2024	RCV000019083.33
Congenital myotonia, autosomal dominant form	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 13, 2016	RCV000184008.5
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Oct 27, 2023	RCV000346725.43
Congenital myotonia, autosomal dominant form Congenital myotonia, autosomal recessive form	Pathogenic (1)	criteria provided, single submitter	Jan 31, 2024	RCV000638232.10
CLCN1-related disorder	Pathogenic (2)	criteria provided, single submitter	Aug 7, 2022	RCV002291268.5
Tip-toe gait	Pathogenic (1)	criteria provided, single submitter	Aug 18, 2020	RCV001548747.3

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 Help 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 Help 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 Help 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.
Pathogenic (Oct 13, 2016)	criteria provided, single submitter (HA_assertions_20150911) Method: research	Congenital myotonia, autosomal dominant form Affected status: unknown Allele origin: unknown, maternal	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-HudsonAlpha Accession: SCV000584084.1 First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015	Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1
Pathogenic (Jun 28, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331890.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CLCN1 Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Aug 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CLCN1-related disorder Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002583812.1 First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022	Comment: PS3 PP3 PP1 PS4_Moderate PM3
Pathogenic (Oct 27, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329299.9 First in ClinVar: Dec 06, 2016 Last updated: Nov 25, 2023	Comment: Published functional studies suggest F413C results in reduced transport of the CLCN1 protein out of the endoplasmic reticulum (PMID: 17990293); In silico analysis supports that … (more) Published functional studies suggest F413C results in reduced transport of the CLCN1 protein out of the endoplasmic reticulum (PMID: 17990293); 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: 1379744, 29790872, 23739125, 10690989, 7981750, 8301644, 9040760, 7951242, 11840191, 31589614, 12390967, 33263785, 18807109, 17932099, 34790634, 32670189, 18337730, 34758253, 34529042, 8533761, 17990293, 21204798) (less)
Pathogenic (Mar 27, 2014)	criteria provided, single submitter (Courtagen Life Sciences Classifications) Method: clinical testing	Myotonia congenita, dominant Affected status: unknown Allele origin: germline	Courtagen Diagnostics Laboratory, Courtagen Life Sciences Accession: SCV000236506.2 First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015
Pathogenic (Feb 28, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715971.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Publications: PubMed (9) PubMed: 1379744‚ 10360989‚ 17990293‚ 21204798‚ 23739125‚ 29790872‚ 18807109‚ 8533761‚ 18337730 Comment: PS3, PS4_moderate, PM3, PP1, PP3 Number of individuals with the variant: 1
Pathogenic (Jun 03, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000612755.4 First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024	Publications: PubMed (16) PubMed: 29050397‚ 24349310‚ 29790872‚ 28325641‚ 29606556‚ 28427807‚ 10690989‚ 11840191‚ 12390967‚ 1379744‚ 17932099‚ 17990293‚ 18807109‚ 21204798‚ 8533761‚ 9040760 Comment: The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families with autosomal recessive … (more) The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families with autosomal recessive myotonia congenita (PMID: 8533761, 21204798), however, it has also been reported in individuals with possible autosomal dominant myotonia congenita (PMID: 11840191, 17932099). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant reduces protein transport from the endoplasmic reticulum (PMID: 17990293). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
Pathogenic (May 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017365.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	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	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000759718.8 First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024	Publications: PubMed (8) PubMed: 28492532‚ 1379744‚ 8533761‚ 11840191‚ 18337730‚ 23739125‚ 10690989‚ 17990293 Comment: This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 413 of the CLCN1 protein … (more) This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 413 of the CLCN1 protein (p.Phe413Cys). This variant is present in population databases (rs121912799, gnomAD 0.2%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 1379744, 8533761, 11840191, 18337730, 23739125). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17531). 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: 10690989, 17990293). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Congenital myotonia, autosomal recessive form (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences Accession: SCV005038730.1 First in ClinVar: May 07, 2024 Last updated: May 07, 2024	Publications: PubMed (1) PubMed: 1379744 Comment: The c.1238T>G (p.(Phe413Cys)) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita, who carried also another Likely pathogenic variant in … (more) The c.1238T>G (p.(Phe413Cys)) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita, who carried also another Likely pathogenic variant in heterozygous state (c.2680C>T). The c.1238T>G variant is listed as a disease-causing in the HGMD database (CM920197) and it has been published for the first time in PMID: 1379744. GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.000265. (less) Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Aug 18, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tip-toe gait Affected status: yes Allele origin: unknown	Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino Accession: SCV001763566.2 First in ClinVar: Aug 07, 2021 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 37091313 Comment: Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal … (more) Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. (less) Clinical Features: Lower limb pain (present) , Pes cavus (present) , limited range of motion of the upper ankle (present) Age: 40-49 years Sex: female Method: Gene panel analysis
Pathogenic (Jul 02, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Congenital myotonia, autosomal recessive form Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005203841.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Publications: PubMed (3) PubMed: 8533761‚ 17990293‚ 38055022 Comment: Variant summary: CLCN1 c.1238T>G (p.Phe413Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: CLCN1 c.1238T>G (p.Phe413Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 251472 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CLCN1 causing Congenital Myotonia, Autosomal Recessive Form, allowing no conclusion about variant significance. The variant c.1238T>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Congenital Myotonia, Autosomal Recessive Form (e.g. Meyer-Kleine_1995, Periviita_2024). These data indicate that the variant is very likely to be associated with disease. A publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in retention of the protein product in the endoplasmic reticulum (Papponen_2008). The following publications have been ascertained in the context of this evaluation (PMID: 8533761, 38055022, 17990293). ClinVar contains an entry for this variant (Variation ID: 17531). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (May 01, 2017)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248207.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Nov 01, 1993)	no assertion criteria provided Method: literature only	MYOTONIA CONGENITA, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000039371.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2019	Publications: PubMed (2) PubMed: 1379744‚ 8301644 George, A. L., Jr. Personal (more...) George, A. L., Jr. Personal Communication. 1997. Nashville, Tenn. Comment on evidence: In 3 brothers with autosomal recessive generalized myotonia congenita (Becker disease; 255700), born of consanguineous parents, Koch et al. (1992) identified a homozygous T-to-G transversion … (more) In 3 brothers with autosomal recessive generalized myotonia congenita (Becker disease; 255700), born of consanguineous parents, Koch et al. (1992) identified a homozygous T-to-G transversion in the CLCN1 gene, resulting in a phe413-to-cys (F413C) substitution toward the end of putative membrane span D8. This residue lies in a highly conserved region of the channel protein that is predicted to form a membrane-spanning alpha helix and possibly a component of the permeation pore (George et al., 1993). Koch et al. (1993) found the F413C missense mutation in 15% of chromosomes carrying a gene for recessive myotonia congenita. (less)
Likely pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Congenital myotonia, autosomal dominant form Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760194.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
Pathogenic (Mar 13, 2024)	no assertion criteria provided Method: clinical testing	CLCN1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005363923.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The CLCN1 c.1238T>G variant is predicted to result in the amino acid substitution p.Phe413Cys. This variant has been reported in multiple unrelated individuals with myotonia … (more) The CLCN1 c.1238T>G variant is predicted to result in the amino acid substitution p.Phe413Cys. This variant has been reported in multiple unrelated individuals with myotonia congenita (Koch et al. 1992. PubMed ID: 1379744; Papponen et al. 2008. PubMed ID: 17990293; Suominen et al. 2008. PubMed ID: 18807109; Brugnoni et al. 2013. PubMed ID: 23739125). This variant is reported in 0.25% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Comment:

Published functional studies suggest F413C results in reduced transport of the CLCN1 protein out of the endoplasmic reticulum (PMID: 17990293); 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: 1379744, 29790872, 23739125, 10690989, 7981750, 8301644, 9040760, 7951242, 11840191, 31589614, 12390967, 33263785, 18807109, 17932099, 34790634, 32670189, 18337730, 34758253, 34529042, 8533761, 17990293, 21204798)

Comment:

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families with autosomal recessive myotonia congenita (PMID: 8533761, 21204798), however, it has also been reported in individuals with possible autosomal dominant myotonia congenita (PMID: 11840191, 17932099). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant reduces protein transport from the endoplasmic reticulum (PMID: 17990293). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.

Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 413 of the CLCN1 protein (p.Phe413Cys). This variant is present in population databases (rs121912799, gnomAD 0.2%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 1379744, 8533761, 11840191, 18337730, 23739125). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17531). 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: 10690989, 17990293). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.1238T>G (p.(Phe413Cys)) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita, who carried also another Likely pathogenic variant in heterozygous state (c.2680C>T). The c.1238T>G variant is listed as a disease-causing in the HGMD database (CM920197) and it has been published for the first time in PMID: 1379744. GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.000265.

Comment:

Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.

Comment:

Variant summary: CLCN1 c.1238T>G (p.Phe413Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 251472 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CLCN1 causing Congenital Myotonia, Autosomal Recessive Form, allowing no conclusion about variant significance. The variant c.1238T>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Congenital Myotonia, Autosomal Recessive Form (e.g. Meyer-Kleine_1995, Periviita_2024). These data indicate that the variant is very likely to be associated with disease. A publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in retention of the protein product in the endoplasmic reticulum (Papponen_2008). The following publications have been ascertained in the context of this evaluation (PMID: 8533761, 38055022, 17990293). ClinVar contains an entry for this variant (Variation ID: 17531). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The CLCN1 c.1238T>G variant is predicted to result in the amino acid substitution p.Phe413Cys. This variant has been reported in multiple unrelated individuals with myotonia congenita (Koch et al. 1992. PubMed ID: 1379744; Papponen et al. 2008. PubMed ID: 17990293; Suominen et al. 2008. PubMed ID: 18807109; Brugnoni et al. 2013. PubMed ID: 23739125). This variant is reported in 0.25% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A retrospective study of accuracy and usefulness of electrophysiological exercise tests.	Periviita V	Journal of neurology	2024	PMID: 38055022
NGS-Panel Diagnosis Developed for the Differential Diagnosis of Idiopathic Toe Walking and Its Application for the Investigation of Possible Genetic Causes for the Gait Anomaly.	Pomarino D	Global medical genetics	2023	PMID: 37091313
Genomic sequencing identifies secondary findings in a cohort of parent study participants.	Thompson ML	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29790872
Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands.	Stunnenberg BC	Neuromuscular disorders : NMD	2018	PMID: 29606556
The antimyotonic effect of lamotrigine in non-dystrophic myotonias: a double-blind randomized study.	Andersen G	Brain : a journal of neurology	2017	PMID: 29050397
Targeted Next Generation Sequencing in patients with Myotonia Congenita.	Ferradini V	Clinica chimica acta; international journal of clinical chemistry	2017	PMID: 28427807
Spectrum of Nondystrophic Skeletal Muscle Channelopathies in Children.	Al-Ghamdi F	Pediatric neurology	2017	PMID: 28325641
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
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
Myotonia congenita and myotonic dystrophy in the same family: coexistence of a CLCN1 mutation and expansion in the CNBP (ZNF9) gene.	Sun C	Clinical genetics	2011	PMID: 21204798
High frequency of co-segregating CLCN1 mutations among myotonic dystrophy type 2 patients from Finland and Germany.	Suominen T	Journal of neurology	2008	PMID: 18807109
In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia.	Trip J	European journal of human genetics : EJHG	2008	PMID: 18337730
F413C and A531V but not R894X myotonia congenita mutations cause defective endoplasmic reticulum export of the muscle-specific chloride channel CLC-1.	Papponen H	Muscle & nerve	2008	PMID: 17990293
Chloride channel myotonia: exon 8 hot-spot for dominant-negative interactions.	Fialho D	Brain : a journal of neurology	2007	PMID: 17932099
Novel CLCN1 mutations with unique clinical and electrophysiological consequences.	Wu FF	Brain : a journal of neurology	2002	PMID: 12390967
Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia.	Sun C	European journal of human genetics : EJHG	2001	PMID: 11840191
Functional consequences of chloride channel gene (CLCN1) mutations causing myotonia congenita.	Zhang J	Neurology	2000	PMID: 10690989
Are you as wealthy as you should be?	Lee G	Canadian journal of gastroenterology = Journal canadien de gastroenterologie	1999	PMID: 10360989
Inheritance of three distinct muscle chloride channel gene (CLCN1) mutations in a single recessive myotonia congenita family.	Sloan Brown K	Neurology	1997	PMID: 9040760
Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia.	Meyer-Kleine C	American journal of human genetics	1995	PMID: 8533761
Evidence for genetic homogeneity in autosomal recessive generalised myotonia (Becker).	Koch MC	Journal of medical genetics	1993	PMID: 8301644
The skeletal muscle chloride channel in dominant and recessive human myotonia.	Koch MC	Science (New York, N.Y.)	1992	PMID: 1379744
George, A. L., Jr. Personal Communication. 1997. Nashville, Tenn.	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CLCN1	-	-	-	-
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Text-mined citations for rs121912799 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000083.3(CLCN1):c.1238T>G (p.Phe413Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121912799 ...