7-143332490-T-G

Variant names:

• chr7-143332490-T-G
• rs121912799
• NM_000083.3:c.1238T>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PP2 PP5_Very_Strong

The NM_000083.3(CLCN1):​c.1238T>G​(p.Phe413Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000263 in 1,613,758 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 5.80
• Publications: 34 publications found

Genes affected

CLCN1 (HGNC:2019): (chloride voltage-gated channel 1) The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

CLCN1 Gene-Disease associations (from GenCC):

• myotonia congenita, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• myotonia congenita, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Thomsen and Becker disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000083.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 0.21191 (below the threshold of 3.09). Trascript score misZ: 0.95247 (below the threshold of 3.09). GenCC associations: The gene is linked to myotonia congenita, autosomal dominant, myotonia congenita, autosomal recessive, Thomsen and Becker disease.
• PP5: Variant 7-143332490-T-G is Pathogenic according to our data. Variant chr7-143332490-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000083.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	NM_000083.3	MANE Select	c.1238T>G	p.Phe413Cys	missense	Exon 11 of 23	NP_000074.3
	CLCN1	NR_046453.2		n.1343T>G		non_coding_transcript_exon	Exon 11 of 22

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.1238T>G	p.Phe413Cys	missense	Exon 11 of 23	ENSP00000339867.2
	CLCN1	ENST00000432192.6	TSL:1	n.*523T>G		non_coding_transcript_exon	Exon 11 of 23	ENSP00000395949.2
	CLCN1	ENST00000432192.6	TSL:1	n.*523T>G		3_prime_UTR	Exon 11 of 23	ENSP00000395949.2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000370 AC: 93 AN: 251472 AF XY: 0.000331

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00189

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000265 AC: 387 AN: 1461572 Hom.: 1 Cov.: 31 AF XY: 0.000242 AC XY: 176 AN XY: 727126

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 50 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00195 AC: 104 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000194 AC: 216 AN: 1111726

Other (OTH) AF: 0.000248 AC: 15 AN: 60380

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74372

African (AFR) AF: 0.0000724 AC: 3 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000341 Hom.: 1

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000321 AC: 39

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Feb 28, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_moderate, PM3, PP1, PP3

May 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 24, 2025

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 03, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed multiple times with a pathogenic variant in unrelated patients with CLCN1-related myotonia congenita referred for genetic testing at GeneDx and in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) alleles in some cases (PMID: 32670189, 8533761, 11840191); Observed in homozygous state or with no identifiable second variant in patients with CLCN1-related myotonia congenita in published literature and not observed in homozygous state in controls (PMID: 1379744, 11840191); 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, 38758368, 29790872, 23739125, 10690989, 7981750, 8301644, 9040760, 7951242, 11840191, 31589614, 12390967, 33263785, 18807109, 17932099, 34790634, 18337730, 34758253, 34529042, 17990293, 8533761, 36796140, 37355912, 38270354, 36978159, 38055022, 32670189, 21204798)

Jun 28, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 03, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:3

Feb 07, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Mar 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myotonia, autosomal dominant form Pathogenic:3

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 13, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Mar 27, 2014

Courtagen Diagnostics Laboratory, Courtagen Life Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myotonia, autosomal recessive form Pathogenic:3

Nov 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jul 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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.

CLCN1-related disorder Pathogenic:2

Aug 07, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3 PP3 PP1 PS4_Moderate PM3

Mar 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Tip-toe gait Pathogenic:1

Aug 18, 2020

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.99
MPC		0.89
ClinPred		0.50	D
GERP RS		5.3
Varity_R		0.82
gMVP		0.87
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121912799; hg19: chr7-143029583;