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
Consequence
NM_000083.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CLCN1 | ENST00000343257.7 | c.2680C>T | p.Arg894* | stop_gained | Exon 23 of 23 | 1 | NM_000083.3 | ENSP00000339867.2 | ||
| CLCN1 | ENST00000432192.6 | n.*1965C>T | non_coding_transcript_exon_variant | Exon 23 of 23 | 1 | ENSP00000395949.2 | ||||
| CLCN1 | ENST00000432192.6 | n.*1965C>T | 3_prime_UTR_variant | Exon 23 of 23 | 1 | ENSP00000395949.2 | ||||
| CLCN1 | ENST00000650516.2 | c.2680C>T | p.Arg894* | stop_gained | Exon 23 of 23 | ENSP00000498052.2 |
Frequencies
GnomAD3 genomes 0.00266 AC: 405AN: 152154Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00288 AC: 716AN: 248982Hom.: 6 AF XY: 0.00278 AC XY: 375AN XY: 134830
GnomAD4 exome AF: 0.00222 AC: 3242AN: 1461892Hom.: 12 Cov.: 32 AF XY: 0.00219 AC XY: 1594AN XY: 727248
GnomAD4 genome 0.00267 AC: 406AN: 152272Hom.: 1 Cov.: 32 AF XY: 0.00289 AC XY: 215AN XY: 74450
ClinVar
Submissions by phenotype
not provided Pathogenic:10
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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. -
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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) -
PP1, PP5, PM3, PS3, PS4, PVS1 -
CLCN1: PP1:Strong, PS3:Moderate, PS4:Moderate, PVS1:Moderate -
Congenital myotonia, autosomal recessive form Pathogenic:9
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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/. -
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This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM3_STR. -
PVS1, PP3, PP4, PP5 -
Criteria applied: PM3_VSTR,PVS1_MOD,PS3_MOD -
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 -
PM2_supp, PVS1_mod, PS3, PS4_mod -
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. -
Congenital myotonia, autosomal dominant form Pathogenic:5
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. -
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Criteria applied: PM3_VSTR,PVS1_MOD,PS3_MOD -
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:4
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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. -
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. -
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Batten-Turner congenital myopathy Pathogenic:1Other:1
Associated with autosomal recessive and autosomal dominant mode of inheritance -
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
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Tip-toe gait Pathogenic:1
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
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. -
Cerebral palsy Pathogenic:1
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at