ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.2680C>T (p.Arg894Ter)

gnomAD frequency: 0.00561  dbSNP: rs55960271
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Total submissions: 27
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000292791 SCV000329301 pathogenic not provided 2021-03-15 criteria provided, single submitter clinical testing 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)
Illumina Laboratory Services, Illumina RCV000020107 SCV000467134 pathogenic Batten-Turner congenital myopathy 2018-05-07 criteria provided, single submitter 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.
Athena Diagnostics Inc RCV000292791 SCV000612784 pathogenic not provided 2023-07-05 criteria provided, single submitter 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.
Invitae RCV000627759 SCV000636295 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2024-01-31 criteria provided, single submitter 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 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000626582 SCV000747283 likely pathogenic Myopathy; EMG: myopathic abnormalities 2017-01-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000019099 SCV000966882 pathogenic Congenital myotonia, autosomal dominant form 2018-08-09 criteria provided, single submitter 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.
Baylor Genetics RCV000627759 SCV000992751 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2012-10-17 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000292791 SCV001248214 pathogenic not provided 2023-11-01 criteria provided, single submitter clinical testing CLCN1: PP1:Strong, PS3:Moderate, PS4:Moderate, PVS1:Moderate
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000019098 SCV001367211 pathogenic Congenital myotonia, autosomal recessive form 2020-03-28 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM3_STR.
Institute of Human Genetics, University of Leipzig Medical Center RCV000019099 SCV001428781 pathogenic Congenital myotonia, autosomal dominant form 2023-09-26 criteria provided, single submitter clinical testing Criteria applied: PM3_VSTR,PVS1_MOD,PS3_MOD
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000292791 SCV001447748 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital RCV000292791 SCV001449784 likely pathogenic not provided 2015-05-12 criteria provided, single submitter clinical testing
Neurogenetics Research Program, University of Adelaide RCV001794458 SCV001737576 pathogenic Cerebral palsy 2021-06-10 criteria provided, single submitter research Diagnosed with cystic fibrosis (p.P508del). Reduced fetal movement and fetal distress syndrome, CLCN1 variant interpreted as contributing to complex phenotype.
Kariminejad - Najmabadi Pathology & Genetics Center RCV001813999 SCV001755308 pathogenic Abnormality of the musculature 2021-07-10 criteria provided, single submitter clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino RCV001564017 SCV001786716 likely pathogenic Tip-toe gait 2021-03-04 criteria provided, single submitter 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].
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000019098 SCV001976940 pathogenic Congenital myotonia, autosomal recessive form 2021-10-01 criteria provided, single submitter clinical testing PVS1, PP3, PP4, PP5
Revvity Omics, Revvity Omics RCV000292791 SCV002023245 pathogenic not provided 2023-09-25 criteria provided, single submitter clinical testing
Mendelics RCV000019099 SCV002518713 pathogenic Congenital myotonia, autosomal dominant form 2022-05-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000019098 SCV002555960 pathogenic Congenital myotonia, autosomal recessive form 2022-06-17 criteria provided, single submitter 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.
MGZ Medical Genetics Center RCV000019099 SCV002579211 pathogenic Congenital myotonia, autosomal dominant form 2022-07-28 criteria provided, single submitter clinical testing
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town RCV000019098 SCV004100819 pathogenic Congenital myotonia, autosomal recessive form 2023-11-02 criteria provided, single submitter research PM2_supporting: the highest population allele frequency in gnomAD v2.1.1 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.
Institute of Human Genetics, University Hospital of Duesseldorf RCV000019098 SCV004171140 pathogenic Congenital myotonia, autosomal recessive form criteria provided, single submitter not provided
OMIM RCV000019098 SCV000039386 pathogenic Congenital myotonia, autosomal recessive form 2009-05-01 no assertion criteria provided literature only
OMIM RCV000019099 SCV000039387 pathogenic Congenital myotonia, autosomal dominant form 2009-05-01 no assertion criteria provided literature only
GeneReviews RCV000020107 SCV000040427 not provided Batten-Turner congenital myopathy no assertion provided literature only Associated with autosomal recessive and autosomal dominant mode of inheritance
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000292791 SCV002037342 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000292791 SCV002038260 pathogenic not provided no assertion criteria provided clinical testing

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