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

dbSNP: rs768119034

Total submissions: 15

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 Inc	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).
Invitae	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	2021-09-01	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.
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	2023-11-02	criteria provided, single submitter	research	PM2_supporting: this variant is absent from gnomAD v2.1.1 (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.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV002259330	SCV004171141	pathogenic	Congenital myotonia, autosomal recessive form		criteria provided, single submitter	not provided
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