ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1261dup (p.Arg421fs)

dbSNP: rs763633152
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000516577 SCV000612757 pathogenic not provided 2023-05-05 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been reported in multiple families with autosomal recessive myotonia congenita (PMID: 29606556, 8533761).
Labcorp Genetics (formerly Invitae), Labcorp RCV000691433 SCV000819211 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2024-01-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg421Profs*9) 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 (rs763633152, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 8533761). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as 1262insC. ClinVar contains an entry for this variant (Variation ID: 447048). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193451 SCV001362283 pathogenic Congenital myotonia, autosomal recessive form 2019-05-24 criteria provided, single submitter clinical testing Variant summary: CLCN1 c.1261dupC (p.Arg421ProfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.8e-05 in 251658 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with Congenital and generalized myotonia in an autosomal recessive form (Meyer-Kleine_1995, Stunnenberg_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV000516577 SCV002017370 pathogenic not provided 2020-11-05 criteria provided, single submitter clinical testing
GeneDx RCV000516577 SCV002097433 pathogenic not provided 2022-08-11 criteria provided, single submitter clinical testing 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8533761, 31589614, 35170402, 35350395)
Fulgent Genetics, Fulgent Genetics RCV000691433 SCV002799217 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2022-01-28 criteria provided, single submitter clinical testing

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.