NM_000083.3:c.1238T>G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 5.80

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a helix (size 2) in uniprot entity CLCN1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000083.3

PP5

Variant 7-143332490-T-G is Pathogenic according to our data. Variant chr7-143332490-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143332490-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3 link	c.1238T>G	p.Phe413Cys	missense_variant	Exon 11 of 23	ENST00000343257.7	NP_000074.3	P35523
CLCN1	NR_046453.2 link	n.1343T>G		non_coding_transcript_exon_variant	Exon 11 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLCN1	ENST00000343257.7 link	c.1238T>G	p.Phe413Cys	missense_variant	Exon 11 of 23	1	NM_000083.3	ENSP00000339867.2	P35523
CLCN1	ENST00000432192.6 link	n.*523T>G		non_coding_transcript_exon_variant	Exon 11 of 23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000432192.6 link	n.*523T>G		3_prime_UTR_variant	Exon 11 of 23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000650516.2 link	c.1238T>G	p.Phe413Cys	missense_variant	Exon 11 of 23			ENSP00000498052.2	A0A3B3IU72

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000370

AC:

AN:

251472

Hom.:

AF XY:

0.000331

AC XY:

AN XY:

135914

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000242

AC XY:

176

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00195

Gnomad4 NFE exome

AF:

0.000194

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000250

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000334

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000321

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

May 18, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 32670189, 18337730, 34758253, 34529042, 17990293, 8533761, 21204798, 36796140, 37355912, 38270354, 36978159, 38055022) -

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 -

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. -

Jun 28, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Mar 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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

- -

Mar 27, 2014

Courtagen Diagnostics Laboratory, Courtagen Life Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

Congenital myotonia, autosomal recessive form

Pathogenic:3

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. -

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. -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.62

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-7.4

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MVP

0.99

MPC

0.89

ClinPred

0.50

GERP RS

5.3

Varity_R

0.82

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over