ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.920T>C (p.Phe307Ser) (rs80356701)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483128 SCV000567635 pathogenic not provided 2018-12-05 criteria provided, single submitter clinical testing The F307S variant in the CLCN1 gene was previously reported in multiple unrelated families with myotonia congenita, in association with both autosomal dominant and autosomal recessive inheritance (Kubisch et al., 1998; Colding-Jørgensen et al., 2003; Fialho et al., 2007). Functional characterization of F307S in Xenopus oocytes showed that voltage dependence was shifted towards positive potentials and the altered protein displayed a dominant-negative effect when expressed with wild type protein (Kubisch et al., 1998). The F307S variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. F307S 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 (R304S, G305E, F306L, T310M) 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, F307S is considered a pathogenic variant.
Athena Diagnostics Inc RCV000483128 SCV000612804 pathogenic not provided 2015-10-21 criteria provided, single submitter clinical testing
Invitae RCV000477848 SCV000759738 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2019-04-12 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 307 of the CLCN1 protein (p.Phe307Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs80356701, ExAC 0.03%). This variant has been reported in the heterozygous, compound heterozygous and homozygous state in individuals affected with myotonia congenita (PMID: 9736777, 17932099, 23152584, 23516313). This variant has also been observed on the opposite chromosome (in trans) from pathogenic variants in multiple individuals affected with autosomal recessive myotonia congenita (PMID: 17932099). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 21050). Experimental studies have shown that this missense change impacts the function of the CLCN1 voltage-dependent chloride channel (PMID: 9736777, 11408615). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000020118 SCV000915213 pathogenic Myotonia congenita 2018-11-18 criteria provided, single submitter clinical testing The CLCN1 c.920T>C (p.Phe307Ser) variant is a missense variant that has been reported in at least 12 unrelated individuals with myotonia congenita (Kubisch et al. 1998; Sun et al. 2001; Colding-Jorgensen et al. 2003; Fialho et al. 2007; Raheem et al. 2012; Horga et al. 2013). In the majority of cases, the variant acted in an autosomal dominant manner, but several of cases of compound heterozygosity and autosomal recessive inheritance were also reported. The p.Phe307Ser variant was absent from 50 controls but is reported at a frequency of 0.000155 in the European (Finnish) population of the Genome Aggregation Database. Functional studies in Xenopus oocytes showed a shifted voltage dependence of the variant channel that was expected to prevent efficient repolarization of the muscle action potential, a finding that has been seen with other disease-causing variants. (Kubisch et al. 1998; Aromataris et al. 2001). Based on the collective evidence, the p.Phe307Ser 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.
GeneReviews RCV000020118 SCV000040438 pathologic Myotonia congenita 2011-04-12 no assertion criteria provided curation Converted during submission to Pathogenic.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477848 SCV000536752 likely pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2016-05-12 no assertion criteria provided research

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