ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.2926C>T (p.Arg976Ter) (rs142539932)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000180791 SCV000568788 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing The R976X variant in the CLCN1 gene has been reported previously in autosomal recessive myotonia congenita, in a family where affected individuals were compound heterozygous for the R976X variant and another variant (Modoni et al., 2011). The R976X variant has also been reported in an individual with epilepsy (Chen et al., 2013), and in an individual with myotonia, however this individual also harbored a variant in the SCN4A gene (Furby et al., 2014). Although not present in the homozygous state, the NHLBI Exome Sequencing Project reports that R976X was observed in 10/4406 alleles (0.23%) from individuals of African American background, indicating it may be a rare variant in this population. We interpret R976X as a variant of uncertain significance.
Invitae RCV000535831 SCV000636324 uncertain significance Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2018-11-13 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the CLCN1 mRNA at codon 976 (p.Arg976*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 13 amino acids of the CLCN1 protein. This variant is present in population databases (rs142539932, ExAC 0.2%). This variant has been reported in individuals affected with myotonia congenita (PMID: 21221019, 25088311). It has also been shown to arise de novo in an individual affected with myotonia and epilepsy (PMID: 23408874). ClinVar contains an entry for this variant (Variation ID: 199652). Experimental studies have not been reported for this truncating variant and it is currently unknown if the last 13 amino acids of the CLCN1 protein are critical for its function. In summary, this is a rare truncation with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
OMIM RCV000180791 SCV000233279 uncertain significance not provided 2013-03-19 no assertion criteria provided literature only
GeneReviews RCV000195160 SCV000243886 pathogenic Myotonia congenita 2015-08-06 no assertion criteria provided literature only

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