ClinVar Miner

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

gnomAD frequency: 0.00070  dbSNP: rs142539932
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000180791 SCV000568788 uncertain significance not provided 2024-04-17 criteria provided, single submitter clinical testing Reported previously with a second variant in patients with myotonia congenita in published literature; however, it is not known whether these variants are on the same allele (in cis) or on different alleles (in trans) (PMID: 21221019, 34529042, 33263785); Reported previously as a heterozygous variant in patient with pain, stiffness, cramping in hands, and severe respiratory problems; no second variant was mentioned and segregation information was not provided (PMID: 36540316); Nonsense variant predicted to result in protein truncation as the last 13 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 20301529, 25964741, 25012387, 23739125, 26471370, 25088311, 25065301, 32010054, 34426522, 33263785, 36540316, 23408874, 21221019, 34529042)
Labcorp Genetics (formerly Invitae), Labcorp RCV000535831 SCV000636324 uncertain significance Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2022-09-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg976*) in the CLCN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 13 amino acid(s) of the CLCN1 protein. This variant is present in population databases (rs142539932, gnomAD 0.2%). This premature translational stop signal has been observed in individuals with clinical features of autosomal recessive myotonia congenita (PMID: 21221019, 33263785). ClinVar contains an entry for this variant (Variation ID: 199652). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Revvity Omics, Revvity RCV000180791 SCV003832362 uncertain significance not provided 2022-12-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003488433 SCV004241429 uncertain significance not specified 2024-10-14 criteria provided, single submitter clinical testing Variant summary: CLCN1 c.2926C>T (p.Arg976X) results in a premature termination codon, predicted to cause a truncation of the encoded protein by removing the last 13 amino acids. No pathogenic variants have been observed downstream. The variant allele was found at a frequency of 0.00021 in 1613610 control chromosomes in the gnomAD database, including 1 homozygote (gnomAD v4.1.0). This frequency is not significantly higher than estimated for a pathogenic variant in CLCN1 causing Myotonia congenita (0.00021 vs 0.0035), allowing no conclusion about variant significance. c.2926C>T has been reported in the literature in individuals affected with Myotonia congenita (e.g., Suetterlin_2022, Modoni_2011, Vereb_2021, Morrow_2013, Chen_2013, Brugnoni_2013) without definitive evidence for causality. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23739125, 23408874, 21221019, 23810313, 34529042, 33263785). ClinVar contains an entry for this variant (Variation ID: 199652). Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM RCV000180791 SCV000233279 uncertain significance not provided 2013-03-19 no assertion criteria provided literature only
GeneReviews RCV000195160 SCV000243886 not provided Batten-Turner congenital myopathy no assertion provided literature only

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