ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1238T>G (p.Phe413Cys) (rs121912799)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000184008 SCV000236506 pathogenic Congenital myotonia, autosomal dominant form 2014-03-27 criteria provided, single submitter clinical testing
GeneDx RCV000346725 SCV000329299 pathogenic not provided 2018-07-24 criteria provided, single submitter clinical testing The F413C pathogenic variant in the CLCN1 gene was previously reported in multiple unrelated families with myotonia congenita, most often in association with autosomal recessive inheritance, although this variant has been identified in individuals with a diagnosis of myotonia congenita and no identifiable second variant (Koch et al., 1992; Koch et al., 1993; Sun et al., 2001). The F413C variant was also identified in multiple members of a family with myotonic dystrophy type 2 (DM2), and it was suggested that F413C may exacerbate the symptoms of DM2 (Sun et al., 2011). Functional studies suggest F413C results in reduced transport of the CLCN1 protein out of the endoplasmic reticulum (Papponen et al., 2008). The F413C variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The F413C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with CLCN1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, F413C is considered a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000346725 SCV000331890 pathogenic not provided 2016-06-28 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000184008 SCV000584084 pathogenic Congenital myotonia, autosomal dominant form 2016-10-13 criteria provided, single submitter research
Athena Diagnostics Inc RCV000346725 SCV000612755 pathogenic not provided 2015-04-02 criteria provided, single submitter clinical testing
Invitae RCV000638232 SCV000759718 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 413 of the CLCN1 protein (p.Phe413Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is present in population databases (rs121912799, ExAC 0.2%). This variant has been reported in the homozygous or compound heterozygous state in many families and individuals affected with myotonia congenita (PMID: 1379744, 23739125, 18337730, 11840191, 8533761). It has also been observed in some members of a family affected with myotonic dystrophy type 2 caused by CNBP repeat expansions, where it was suggested to exacerbate disease severity (PMID: 21204798). ClinVar contains an entry for this variant (Variation ID: 17531). Experimental studies have shown that this missense change impairs the export of CLCN1 out of the endoplasmic reticulum and affects channel deactivation kinetics (PMID: 10690989, 17990293). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000019083 SCV000039371 pathogenic Congenital myotonia, autosomal recessive form 1993-11-01 no assertion criteria provided literature only

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