ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1437_1450del (p.Pro480fs) (rs768119034)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000395981 SCV000329300 pathogenic not provided 2019-01-09 criteria provided, single submitter clinical testing The c.1437_1450del14 variant in the CLCN1 gene has been reported previously, either in the homozygous state or in trans with another pathogenic variant, in individuals with autosomal recessive generalized myotonia, Becker phenotype (Meyer-Kleine et al., 1994; Lehmann-Horn et al., 1995; Brugnoni et al., 2013). It has also been identified in several individuals who were presumed to have autosomal recessive generalized myotonia but did not have a second identifiable variant, as well as in mildly affected family members without a second variant and with EMG myotonia (Meyer-Kleine et al., 1994; Lehmann-Horn et al., 1995). The c.1437_1450del14 variant causes a frameshift starting with codon Proline 480, which changes this amino acid to a Histidine residue and creates a premature Stop codon at position 24 of the new reading frame, denoted p.P480HfsX24. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1437_1450del14 variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1437_1450del14 as a pathogenic variant.
Athena Diagnostics Inc RCV000395981 SCV000612762 pathogenic not provided 2020-06-29 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. 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 RCV000552780 SCV000636291 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2020-10-16 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in the homozygous or compound heterozygous state in several families and individuals affected with myotonia congenita (PMID: 24349310, 18337730, 23739125, 7951215, 22649220). It has also been reported in the heterozygous state in families and individuals affected with myotonia congenita; the clinical significance of this variant for autosomal dominant disease is currently uncertain (PMID: 7951215, 23893571). ClinVar contains an entry for this variant (Variation ID: 279778). Loss-of-function variants in CLCN1 are known to cause autosomal recessive forms of myotonia congenita (PMID: 17932099, 22094069, 23739125). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000778142 SCV000914273 pathogenic Myotonia congenita 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 Praxis fuer Humangenetik Tuebingen RCV000395981 SCV001248209 pathogenic not provided 2020-06-01 criteria provided, single submitter clinical testing
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.
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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.