ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1129C>T (p.Arg377Ter)

gnomAD frequency: 0.00001  dbSNP: rs201714423
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000517902 SCV000612753 pathogenic not provided 2016-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000695020 SCV000823494 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2023-12-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg377*) 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 (rs201714423, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 21221019). ClinVar contains an entry for this variant (Variation ID: 447045). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000517902 SCV002019329 pathogenic not provided 2019-08-02 criteria provided, single submitter clinical testing
GeneDx RCV000517902 SCV005080493 pathogenic not provided 2023-11-10 criteria provided, single submitter clinical testing Reported in association with autosomal recessive myotonia congenita in the published literature (PMID: 28325641, 17932099); Nonsense 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: 31589614, 34938096, 32721234, 17932099, 23893571, 25525159, 31069529, 34529042, 28325641)
Fulgent Genetics, Fulgent Genetics RCV000695020 SCV005667233 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2024-05-15 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004535670 SCV004716978 pathogenic CLCN1-related disorder 2023-11-16 no assertion criteria provided clinical testing The CLCN1 c.1129C>T variant is predicted to result in premature protein termination (p.Arg377*). This variant has been reported in the homozygous or compound heterozygous states in three patients with myotonia congenita (Fialho et al 2007. PubMed ID: 17932099; Modoni et al 2011. PubMed ID: 21221019), and in one patient with myotonia congenita in which a second potentially pathogenic variant was not identified (Sun et al 2020. PubMed ID: 31567646). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-143028708-C-T). Nonsense variants in CLCN1 are expected to be pathogenic. This variant is interpreted as pathogenic.

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