ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.2058C>G (p.Tyr686Ter)

gnomAD frequency: 0.00001  dbSNP: rs1417174086
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 RCV001008657 SCV001168436 likely pathogenic not provided 2019-02-20 criteria provided, single submitter clinical testing The Y686X pathogenic variant in the CLCN1 gene has been reported previously in an individual described as having autosomal recessive myotonia congenita, but was seen with a variant that is not classified as pathogenic and segregation information was not provided (Modoni et al., 2011). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies suggested an effect of Y686X on chloride currents, but the methods used in these studies were not clearly described (Desaphy et al., 2013). The Y686X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret Y686X as a likely pathogenic variant.
Invitae RCV003769412 SCV004587590 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2023-08-23 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects CLCN1 function (PMID: 23933576). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 817516). This premature translational stop signal has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 21221019). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Tyr686*) 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).

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.