7-143351678-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_000083.3(CLCN1):​c.2680C>T​(p.Arg894*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,614,164 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0022 ( 12 hom. )

Consequence

CLCN1
NM_000083.3 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:34O:1

Conservation

PhyloP100: 1.07
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
PP5
Variant 7-143351678-C-T is Pathogenic according to our data. Variant chr7-143351678-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143351678-C-T is described in Lovd as [Pathogenic]. Variant chr7-143351678-C-T is described in Lovd as [Pathogenic]. Variant chr7-143351678-C-T is described in Lovd as [Likely_pathogenic]. Variant chr7-143351678-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLCN1NM_000083.3 linkc.2680C>T p.Arg894* stop_gained Exon 23 of 23 ENST00000343257.7 NP_000074.3 P35523
CLCN1NR_046453.2 linkn.2635C>T non_coding_transcript_exon_variant Exon 22 of 22

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLCN1ENST00000343257.7 linkc.2680C>T p.Arg894* stop_gained Exon 23 of 23 1 NM_000083.3 ENSP00000339867.2 P35523
CLCN1ENST00000432192.6 linkn.*1965C>T non_coding_transcript_exon_variant Exon 23 of 23 1 ENSP00000395949.2 H7C0N6
CLCN1ENST00000432192.6 linkn.*1965C>T 3_prime_UTR_variant Exon 23 of 23 1 ENSP00000395949.2 H7C0N6
CLCN1ENST00000650516.2 linkc.2680C>T p.Arg894* stop_gained Exon 23 of 23 ENSP00000498052.2 A0A3B3IU72

Frequencies

GnomAD3 genomes
AF:
0.00266
AC:
405
AN:
152154
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0156
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00332
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.00288
AC:
716
AN:
248982
Hom.:
6
AF XY:
0.00278
AC XY:
375
AN XY:
134830
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.000993
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0168
Gnomad NFE exome
AF:
0.00286
Gnomad OTH exome
AF:
0.00294
GnomAD4 exome
AF:
0.00222
AC:
3242
AN:
1461892
Hom.:
12
Cov.:
32
AF XY:
0.00219
AC XY:
1594
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00122
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.0172
Gnomad4 NFE exome
AF:
0.00195
Gnomad4 OTH exome
AF:
0.00169
GnomAD4 genome
AF:
0.00267
AC:
406
AN:
152272
Hom.:
1
Cov.:
32
AF XY:
0.00289
AC XY:
215
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0156
Gnomad4 NFE
AF:
0.00334
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00237
Hom.:
3
Bravo
AF:
0.00101
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00128
AC:
11
ExAC
AF:
0.00285
AC:
346
Asia WGS
AF:
0.000577
AC:
3
AN:
3478
EpiCase
AF:
0.00185
EpiControl
AF:
0.00190

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:34Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:10
Jul 21, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect; R894X destabilizes the protein, possibly leading to reduced expression, and greatly reduces chloride currents in vitro (PMID: 8533761, 17990293); Nonsense variant predicted to result in protein truncation, as the last 95 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 22995991, 8845168, 10665666, 27142102, 27614575, 30824560, 32670189, 31216405, 7874130, 20301529, 25508133, 23739125, 18337100, 12661046, 8857733, 23097607, 11840191, 27296017, 28039888, 29424939, 34426522, 34008892, 33013670, 17990293, 38374194, 9576553, 32528171, 34106991, 33263785, 34418069, 35026467, 34529042, 37273706, 36628841, 36796140, 8533761, 15162127, 22197187) -

Jul 05, 2023
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. This variant is one of the most common pathogenic variants identified in myotonia congenita patients worldwide (PMID: 20301529, 11840191) and is statistically more frequent in affected individuals than in the general population and/or healthy controls (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is reported in the literature to segregate recessively in most families; however, cases of dominant segregation are also reported (PMID: 20301529, 11840191, 15162127, 7874130). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 8533761, 17107341). 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. -

Aug 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CLCN1: PP1:Strong, PS3:Moderate, PS4:Moderate, PVS1:Moderate -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 12, 2015
Clinical Genetics and Genomics, Karolinska University Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 13, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 30, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP1, PP5, PM3, PS3, PS4, PVS1 -

Sep 25, 2023
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Congenital myotonia, autosomal recessive form Pathogenic:9
Jul 17, 2023
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. There are no clear phenotype-genotype correlations, however loss of function is generally associated with autosomal recessive inheritance (PMIDs: 20301529, 32117024). (I) 0108 - This gene is associated with both recessive and dominant disease. Recessive myotonia congenita (MIM#255700, Becker disease) is more severe than dominant myotonia congenita (MIM#160800, Thomsen disease). At least twelve variants were reported to cause both diseases (PMIDs: 20301529, 32010054). (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been suggested for pathogenic variants associated with autosomal dominant inheritance (PMIDs: 20301529, 32117024). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial phenotypic variability has been reported (PMID: 20301529). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 (874 heterozygotes, 9 homozygotes). (I) 0703 - Other premature termination variants (PTVs) comparable to the one identified in this case have moderate previous evidence for pathogenicity. At least three PTVs downstream have been reported as likely pathogenic/pathogenic or in affected individuals (ClinVar, PMID: 33263785). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in many individuals with myotonia, with autosomal recessive and autosomal dominant inheritance (ClinVar, PMIDs: 33263785, 34418069, 32670189, 32010054, 33013670, 23893571). It has also been reported as heterozygous in unaffected individuals. (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies using L6 myotubes and rat myofibers showed protein with the variant was exported normally from ER but was unstable (PMID: 17990293). An earlier study showed the variant resulted in a large reduction, but not complete abolition of chloride conductance in Xenopus oocytes (PMID: 8533761). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 01, 2009
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Mar 28, 2020
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM3_STR. -

Oct 01, 2021
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PP3, PP4, PP5 -

Jun 17, 2022
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.2680C>T (p.Arg894X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with myotonia congenita in HGMD. c.2680C>T has been reported in the literature in multiple homozygous, compound heterozygous and heterozygous individuals affected with Congenital Myotonia (Raheem_2012 and Skalova_2013). Individuals who were homozygous for this variant had reduced sarcolemmal ClC-1 expression (Raheem_2012). Functional studies in Xenopus oocytes demonstrated that the variant resulted in greatly reduced chloride currents compared to wild type (Meyer-Kleine_1995). Papponen_2008 have demonstrated that this variant did not inhibit transport of the protein but did cause reduced stability in myotubes. These data indicate that the variant is very likely to be associated with disease. Eighteen submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS(n=1), likely pathogenic(n=4) and pathogenic (n=13). Based on the evidence outlined above, the variant was classified as pathogenic. -

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Institute of Human Genetics, University Hospital of Duesseldorf
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Oct 25, 2024
Institute of Human Genetics, Heidelberg University
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_supp, PVS1_mod, PS3, PS4_mod -

Jun 18, 2024
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PM3_VSTR,PVS1_MOD,PS3_MOD -

May 22, 2024
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.01660 (1.6%; 417/25122 alleles in European Finnish population, including 5 homozygous observations) and gnomAD v3.1.2 is 0.01564 (1.6%; 166/10612 alleles in European Finnish population, including 1 homozygous observation). The heterozygous carrier frequency in gnomAD is calculated to be 0.032, i.e. 1 in 31 individuals in Finnish European population). This carrier frequency is not inconsistent with the reported high frequency of AR myotonia congenital in Scandinavia viz. 7.3 per 100 000 in Northern Finland (PMID 9598722) and 9.4 per 100 000 in Northern Norway (PMID 11840191). PVS1_moderate: nonsense variant not predicted to undergo NMD (occurs in 3' most exon 23). Role of exon 23 in protein function is unknown. At least 3 other pathogenic LOF variants in exon 23 have been identified in patients with AR myotonia congenita. This variant removes <10% of the protein. PM3_verystrong: this variant has been found in a compound heterozygous state in multiple individuals with AR myotonia congenital (>4 points). PS4 met: this variant has been described in more than 10 unrelated probands with autosomal recessive myotonia congenita (both homozygous and compound heterozygous observations) (PMID 11184019). PS3 supporting: functional studies provide supportive evidence that the variant has a damaging effect on the gene or gene product. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. -

Congenital myotonia, autosomal dominant form Pathogenic:5
May 01, 2009
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Sep 26, 2023
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PM3_VSTR,PVS1_MOD,PS3_MOD -

May 04, 2022
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 28, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 09, 2018
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Arg894X variant in CLCN1 has been reported in >25 homozygous and compound heterozygous individuals with clinical features of myotonia congenita and segreg ated with disease in many affected relatives (Brugnoni 2013, Fialho 2007, Mazon 2012, Meyer-Kleine 1995, Neroldova 2016, Sun 2001, Tincheva 2016, Trip 2008, Zie lonka 2012). It is a common pathogenic variant in Scandinavian populations, wher e the disease prevalence is approximately 1 in 10,000 versus 1 in 100,000 worldw ide (Sun 2001). This variant has been identified in 1.63% (429/25792) of Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org) and reported in ClinVar (Variation ID# 17545). This nonsense variant leads to a premature termination codon at position 894. This alteration occurs w ithin the last exon and is more likely to escape nonsense mediated decay (NMD) a nd result in a truncated protein. In vitro functional studies provide some evide nce that the p.Arg894X variant impacts protein function (Meyer-Kleine 1995). In summary, this variant meets criteria to be classified as pathogenic for myotonia congenita in an autosomal recessive manner based upon segregation studies, func tional evidence and predicted impact on protein. ACMG/AMP Criteria applied: PM3_ VeryStrong, PP1_Strong, PS3_Moderate. -

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:4
Oct 17, 2012
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg894*) in the CLCN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the CLCN1 protein. This variant is present in population databases (rs55960271, gnomAD 1.7%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 7874130, 8533761, 8845168, 11840191, 15162127, 18337730, 22094069, 22197187, 24349310, 26096614, 27142102, 27296017, 27614575). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 17545). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CLCN1 function (PMID: 8533761, 17990293). For these reasons, this variant has been classified as Pathogenic. -

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Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

The c.2680C>T (p.(Arg894*)) variant was found in a heterozygous state in 6 Slovak patient with Myotonia congenita, 3 of whom carried also another Likely pathogenic variants in heterozygous state, namely c.1437_1450del, c.1238T>G, and c.1231G>T. The c.2680C>T variant is listed as a disease-causing in the HGMD database (CM940286) and it has been published for the first time in PMID: 7874130. GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.0000315. -

Jun 22, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Batten-Turner congenital myopathy Pathogenic:1Other:1
May 07, 2018
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The CLCN1 c.2680C>T (p.Arg894Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg894Ter variant is well-described in the literature as a common pathogenic variant (Dunø et al. 2015). Across a selection of five studies, the variant was detected in a homozygous state in nine individuals, in a compound heterozygous state in 32 individuals and in a heterozygous state in 12 individuals, all affected with myotonia congenita (Meyer-Kleine et al. 1995; Papponen et al. 1999; Sun et al. 2001; Suominen et al. 2008; Rayan et al. 2012). The variant was present in 1/324 control chromosomes and is reported at a frequency of 0.03 in the Finnish in Finland population of the 1000 Genomes Project. Functional studies in Xenopus oocytes demonstrated that the variant resulted in greatly reduced choride currents compared to wild type, to a level that was intermediate between the reductions seen for a known “fully dominant” pathogenic variant, and a known “fully recessive” pathogenic variant (Meyer-Kleine et al. 1995). Experiments in L6 myotubes and isolated rat myofibers indicated that the variant did not inhibit transport of the protein but did cause reduced stability (Papponen et al. 2008). Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg894Ter variant is classified as pathogenic for the autosomal recessive form of myotonia congenita. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

Associated with autosomal recessive and autosomal dominant mode of inheritance -

Myopathy;C4021726:EMG: myopathic abnormalities Pathogenic:1
Jan 01, 2017
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Tip-toe gait Pathogenic:1
Mar 04, 2021
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino
Significance: Likely pathogenic
Review Status: flagged submission
Collection Method: clinical testing

We examined a family - two daughters and mother. Elder daughter and the mother both have Arg894* variant. Elder daughter is toe-walker. It is not known about the mother whether she had toe-walking in childhood. Younger daughter doesn't have this variant and she is not toe-walker. In the ClinVar database, it is mostly classified as likely pathogenic; 12 entries as pathogenic or probably pathogenic compared to 1 entry as VUS. The variant is described in the literature as causing myotonia congenita of the Thomsen type (autosomal dominant inherited form) and also of the Becker type (autosomal recessive inheritance) [Meyer-Kleine (1995) Am J Hum Genet 57: 1325, Zielonka (2012 ) Neuromuscul Disord 22: 355 and Tincheva (2016) Neuromuscul Disord 26: 675]. Through in-vitro analyzes it could be shown that the detected variant has a dominant-negative effect on the function of the chloride channel [Meyer-Kleine (1995) Am J Hum Genet 57: 1325], which is why c. 2680C> T p. (Arg894 *) both autosomal dominant and recessive inheritance are possible [Pusch (2002) Hum Courage 19: 423]. 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. -

CLCN1-related disorder Pathogenic:1
Aug 05, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The CLCN1 c.2680C>T variant is predicted to result in premature protein termination (p.Arg894*). This variant has an allele frequency of 1.66% in Finnish European population and has been reported in the homozygous state in 9 individuals with unknown phenotype in gnomAD. With some exceptions, a variant like this would not normally be considered to be a primary cause of disease. However, this variant has been well-documented in patients with myotonia congenita in different populations (see, for example, Suominen et al. 2008. PubMed ID: 18807109; Ivanova et al. 2013. PubMed ID: 25438602; Skalova et al. 2013. PubMed ID: 24349310). In particular, this variant has been reported to account for ~55% of affected individuals in a Northern Scandinavian cohort (Table 4 in Brugnoni et al. 2013; PubMed ID: 23739125). Additionally, this variant may act as a recessive or dominant pathogenic variant, probably depending on the genetic background (Duno et al. 2004. PubMed ID: 15162127). It is noteworthy that this is located in the final CLCN1 exon and some mRNAs with this variant may escape nonsense-mediated decay. Functional studies have found that this variant may cause a dramatic reduction, but not a full loss, of chloride currents (Meyer-Kleine et al. 1995. PubMed ID: 8533761). These observations may be consistent with the somewhat high allele frequency and the complex inheritance pattern associated with this variant. In a public database, this variant has also been interpreted as pathogenic by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/17545/). Taken together, the c.2680C>T (p.Arg894*) variant is categorized as pathogenic. -

Abnormality of the musculature Pathogenic:1
Jul 10, 2021
Kariminejad - Najmabadi Pathology & Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cerebral palsy Pathogenic:1
Jun 10, 2021
Neurogenetics Research Program, University of Adelaide
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

Diagnosed with cystic fibrosis (p.P508del). Reduced fetal movement and fetal distress syndrome, CLCN1 variant interpreted as contributing to complex phenotype. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Benign
-0.044
Eigen_PC
Benign
-0.34
FATHMM_MKL
Benign
0.49
N
Vest4
0.68
GERP RS
2.9

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

LitVar

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

Other links and lift over

dbSNP: rs55960271; hg19: chr7-143048771; COSMIC: COSV58367397; COSMIC: COSV58367397; API