7-143351678-C-T

Position:

• chr7-143351678-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_000083.3(CLCN1):​c.2680C>T​(p.Arg894Ter) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R894R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (12 hom.)
• Consequence: CLCN1 NM_000083.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28 O:1
• Conservation: PhyloP100: 1.07

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]

ACMG classification

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 8 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/exons	MANE	UniProt
CLCN1	NM_000083.3	c.2680C>T	p.Arg894Ter	stop_gained	23/23	ENST00000343257.7
CLCN1	NR_046453.2	n.2635C>T		non_coding_transcript_exon_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN1	ENST00000343257.7	c.2680C>T	p.Arg894Ter	stop_gained	23/23	1	NM_000083.3	P4
CLCN1	ENST00000432192.6	c.*1965C>T		3_prime_UTR_variant, NMD_transcript_variant	23/23	1
CLCN1	ENST00000650516.2	c.2680C>T	p.Arg894Ter	stop_gained	23/23			A2

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 405 AN: 152154 Hom.: 1 Cov.: 32

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

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

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

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:28 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 25, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CLCN1: PM3:Very Strong, PVS1:Moderate, PM2:Supporting, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2021	Published functional studies found that although the R894X pathogenic variant did not inhibit transport of the protein, it destabilized the protein, possibly leading to reduced expression (Papponen et al., 2008); Published functional studies also noted that the variant greatly reduces chloride currents in vitro (Meyer-Klein et al., 1995); Nonsense variant in the C-terminus 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 the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 22995991, 8845168, 10665666, 27142102, 27614575, 30824560, 32670189, 31216405, 8533761, 17990293, 22197187, 7874130, 20301529, 25508133, 23739125, 15162127, 18337100, 12661046, 8857733, 23097607, 11840191, 27296017, 28039888, 29424939, 34426522, 34008892, 33263785, 33013670, 9576553, 32528171, 34106991) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	May 12, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 05, 2023	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. -

Congenital myotonia, autosomal recessive form Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -
Pathogenic, criteria provided, single submitter	research	Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	May 22, 2024	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/. -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 17, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 28, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM3_STR. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PVS1, PP3, PP4, PP5 -

Congenital myotonia, autosomal dominant form Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 26, 2023	Criteria applied: PM3_VSTR,PVS1_MOD,PS3_MOD -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 28, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 09, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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 protein 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2012	- -
Pathogenic, criteria provided, single submitter	research	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	-	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. -

Batten-Turner congenital myopathy Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Associated with autosomal recessive and autosomal dominant mode of inheritance -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 07, 2018	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. -

Myopathy;C4021726:EMG: myopathic abnormalities Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Tip-toe gait Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 04, 2021

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. -

Cerebral palsy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Neurogenetics Research Program, University of Adelaide

Jun 10, 2021

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

Abnormality of the musculature Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

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
MutationTaster	Benign	1.0	A
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

Other links and lift over

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