ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.2596-1G>A

gnomAD frequency: 0.00003  dbSNP: rs771721648
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522584 SCV000617775 pathogenic not provided 2024-02-23 criteria provided, single submitter clinical testing Observed with a pathogenic variant in a patient with myotonia congenita in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 34529042); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon 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: 17932099, 34529042)
Labcorp Genetics (formerly Invitae), Labcorp RCV000813032 SCV000953365 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2024-12-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 22 of the CLCN1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs771721648, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 17932099; internal data). 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. ClinVar contains an entry for this variant (Variation ID: 449534). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 RCV000522584 SCV002022567 likely pathogenic not provided 2021-11-28 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000522584 SCV004229540 pathogenic not provided 2023-03-09 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is not expected to cause loss of protein expression through nonsense-mediated decay, however, it is expected to severely disrupt protein function in this gene. This variant appears to segregate with disease in at least one family. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000813032 SCV005667261 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2024-06-01 criteria provided, single submitter clinical testing

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