ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1437_1450del (p.Pro480fs)

dbSNP: rs768119034
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000395981 SCV000329300 pathogenic not provided 2022-02-04 criteria provided, single submitter clinical testing Observed with a pathogenic variant in a patient with myotonia congenita, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Brugnoni et al., 2013); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23113340, 25438602, 7581380, 9040760, 33263785, 31589614, 23739125, 7951215)
Athena Diagnostics RCV000395981 SCV000612762 pathogenic not provided 2023-02-01 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls and therefore is consistent with pathogenicity. This variant is primarily reported as autosomal recessive myotonia congenita (PMID: 17932099, 18337730, 23739125, 24349310), however, it has also been reported as autosomal dominant myotonia congenita (PMID: 23893571).
Labcorp Genetics (formerly Invitae), Labcorp RCV000552780 SCV000636291 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2024-01-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Pro480Hisfs*24) in the CLCN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLCN1 are known to be pathogenic (PMID: 17932099, 22094069, 23739125). This variant is present in population databases (rs768119034, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive myotonia congenita (PMID: 7951215, 18337730, 22649220, 23739125, 24349310). This variant has been reported in individual(s) with autosomal dominant myotonia congenita (PMID: 7951215, 23893571); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 279778). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina RCV000778142 SCV000914273 pathogenic Batten-Turner congenital myopathy 2019-04-05 criteria provided, single submitter clinical testing The CLCN1 c.1437_1450delACCCTGCGGAGGCT (p.Pro480HisfsTer24) variant results in a frameshift variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Pro480HisfsTer24 variant has been reported in at least 14 individuals with myotonia congenita (MC), which includes three in a homozygous state and six in a compound heterozygous state (Meyer-Kleine et al. 1994; Lehmann-Horn et al. 1995; Meyer-Kleine et al. 1995; Mailander et al. 1996; Fialho et al. 2007; Dupre et al. 2009; Raja Rayan et al. 2012; Brugnoni et al. 2013). The variant appears to be associated with an autosomal recessive inheritance pattern, as the majority of evaluated heterozygous family members were unaffected. However, a single clinically unaffected heterozygous male was reported to display latent myotonia (Mailander et al. 1996). Homozygosity for the variant also reportedly results in a more severe phenotype associated with transient weakness and severely reduced chloride conductance in muscle fibers, consistent with features of recessive MC. The p.Pro480HisfsTer24 variant was absent from at least 660 control chromosomes and is reported at a frequency of 0.000150 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Pro480HisfsTer24 variant is classified as pathogenic for myotonia congenita. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen RCV000395981 SCV001248209 pathogenic not provided 2024-04-01 criteria provided, single submitter clinical testing CLCN1: PVS1, PM2, PS4:Moderate
Institute of Human Genetics, University of Leipzig Medical Center RCV001262336 SCV001440160 pathogenic Congenital myotonia, autosomal dominant form 2019-01-01 criteria provided, single submitter clinical testing This variant was identified as compound heterozygous.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001753742 SCV001994822 pathogenic Smith-Lemli-Opitz syndrome 2021-10-28 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000395981 SCV002017366 pathogenic not provided 2023-06-30 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV001262336 SCV002580648 pathogenic Congenital myotonia, autosomal dominant form 2022-01-28 criteria provided, single submitter clinical testing
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town RCV002259330 SCV004100818 pathogenic Congenital myotonia, autosomal recessive form 2024-05-22 criteria provided, single submitter research PM2_supporting: this variant is absent from gnomAD v4.0 (adequate coverage >20X confirmed). The highest population allele frequency in gnomAD v3.1.2 is 0.00016 (0.016%; 11/68038 alleles in European non-Finnish population). PM3_verystrong: this variant has been found in a compound heterozygous state in multiple individuals with AR myotonia congenital (>4 points). PVS1 met: frameshift variant predicted to undergo NMD. Exon is present in a biologically relevant transcript in a gene where LOF is a known mechanism of disease. PS4 met: this variant has been described in more than 10 unrelated probands with consistent phenotype for disorder. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
Institute of Human Genetics, University Hospital of Duesseldorf RCV002259330 SCV004171141 pathogenic Congenital myotonia, autosomal recessive form criteria provided, single submitter not provided
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences RCV002259330 SCV005038722 likely pathogenic Congenital myotonia, autosomal recessive form criteria provided, single submitter research The c.1437_1450del (p.(Pro480Hisfs*24)) variant was found in a heterozygous state in 3 Slovak patients with Myotonia congenita and in all of them also the second Likely Pathogenic variant was found: in two of them it was c.2680C>T (p.(Arg894*), whereas in the last one c.2364+2T>C splicing variant. The c.1437_1450del variant is listed as a disease-causing in the HGMD database (CD941645). GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.000121.
OMIM RCV002259330 SCV000039380 pathogenic Congenital myotonia, autosomal recessive form 2009-05-01 no assertion criteria provided literature only
Institute of Human Genetics, Cologne University RCV000664241 SCV000787809 uncertain significance Autosomal dominant intermediate Charcot-Marie-Tooth disease 2018-04-26 no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV001262336 SCV001749882 not provided Congenital myotonia, autosomal dominant form no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 10-22-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino RCV003319191 SCV004023201 likely pathogenic Tip-toe gait 2022-11-15 no assertion criteria provided clinical testing 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.

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