ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1357C>T (p.Arg453Trp) (rs376026619)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484220 SCV000568786 uncertain significance not provided 2017-01-04 criteria provided, single submitter clinical testing The R453W variant in the CLCN1 gene has been reported along with a second variant in the CLCN1 gene in an individual with myotonia, muscle stiffness, fatigue, muscle cramps, myalgia, generalized muscular hypertrophy with worsening of symptoms in cold temperatures (Portaro et al., 2015). However, functional studies demonstrated that the chloride current in cells transfected with the R453W variant was similar to wild-type (Portaro et al., 2015). The R453W variant was not observed at a significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R453W 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. However, this substitution occurs at a position that is not conserved. We interpret R453W as a variant of uncertain significance.
Invitae RCV000536748 SCV000636304 uncertain significance Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 453 of the CLCN1 protein (p.Arg453Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs376026619, ExAC 0.02%). This variant has been reported with a second variant in an individual affected with myotonia congenita (PMID: 26007199). It has also been reported in another individual affected with myotonia congenita, however it is unknown if a second CLCN1 variant was identified (PMID: 23739125). ClinVar contains an entry for this variant (Variation ID: 420148). Experimental studies have shown that this missense change does not affect channel function in vitro (PMID: 26007199). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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.