NM_000083.3:c.929C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000083.3(CLCN1):c.929C>T(p.Thr310Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T310T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 6.14

Publications

14 publications found

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 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

CLCN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000083.3

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

PP5

Variant 7-143330847-C-T is Pathogenic according to our data. Variant chr7-143330847-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 21051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3 link	c.929C>T	p.Thr310Met	missense_variant	Exon 8 of 23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 link	n.1034C>T		non_coding_transcript_exon_variant	Exon 8 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7 link	c.929C>T	p.Thr310Met	missense_variant	Exon 8 of 23	1	NM_000083.3	ENSP00000339867.2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

251414

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

May 03, 2016

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 06, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate this variants alters open probability of the common gate via reduced opening rate (PMID: 12390967, 12566541); Not observed at significant frequency in large population cohorts (gnomAD); 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: 12390967, 15311340, 19949657, 38720415, Prado2020[CaseReport], 23893571, 15162127, 9566422, 12566541, 18263754, 33263785, 38270354, 34790634, 35170402, 24349310, 20301529, 32670189, 8857733, 8857727, 8571958) -

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

Pathogenic:2

Jun 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 310 of the CLCN1 protein (p.Thr310Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant myotonia congenita (PMID: 12390967, 15311340, 19949657; internal data). This variant has been reported in individual(s) with autosomal recessive myotonia congenita (PMID: 18263754); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 21051). 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 80%. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 12390967, 12566541). For these reasons, this variant has been classified as Pathogenic. -

Congenital myotonia, autosomal dominant form

Pathogenic:1

Jun 06, 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.929C>T (p.Thr310Met) 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 1.9e-06 in 1614076 control chromosomes. c.929C>T has been reported in the literature in the heterozygous state in multiple individuals affected with autosomal dominant myotonia (e.g. Wu_2002, Jacobsen_2024, Meyer_2020, Jou_2004, Bernard_2021, Vereb_2021, Moon_2009) and in the homozygous state in at least one individual with more severe symptoms of myotonia (e.g. Bernard_2021). These data indicate that the variant is very likely to be associated with disease. Experimental studies show that this variant impacts CIC-1 gating in vitro (e.g. Wu_2002, Duffield_2003). The following publications have been ascertained in the context of this evaluation (PMID: 18263754, 12566541, 38270354, 15311340, 32670189, 19949657, 33263785, 12390967). ClinVar contains an entry for this variant (Variation ID: 21051). Based on the evidence outlined above, the variant was classified as pathogenic in association with autosomal dominant myotonia. -

Congenital myotonia, autosomal recessive form

Pathogenic:1

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant p.T310M in CLCN1 (NM_000083.3) has been reported both in autosomal dominant as well as recessive myotonia congenita (Bernard G et al; Wu Fen-Fen et al).Functional studies suggest a damaging effect by affecting the opening rate (Duffield M et al). It has been submitted to ClinVar as Pathogenic. It is novel (not in any individuals) in gnomAD Exomes and 1000 Genome. The p.T310M missense variant is predicted to be damaging by both SIFT and PolyPhen2 and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic. -

Batten-Turner congenital myopathy

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Associated with autosomal recessive and autosomal dominant mode of inheritance -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

.;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Benign

1.0

.;L

PhyloP100

6.1

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.5

.;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0040

.;D

Sift4G

Uncertain

0.0070

.;D

Polyphen

1.0

.;D

Vest4

0.84

MutPred

0.82

Loss of catalytic residue at T310 (P = 0.0895);Loss of catalytic residue at T310 (P = 0.0895);

MVP

0.98

MPC

0.72

ClinPred

0.98

GERP RS

4.6

Varity_R

0.65

gMVP

0.76

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over