ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.2596-1G>A (rs771721648)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522584 SCV000617775 pathogenic not provided 2016-01-05 criteria provided, single submitter clinical testing The c.2596-1 G>A splice site variant has been reported previously in two compound heterozygous siblings with myotonia congenita (Fialho et al., 2007). The c.2596-1 G>A variant destroys the canonical splice acceptor site in intron 22. It is predicted to cause abnormal splicing, either leading to an abnormal message that is subject to nonsense mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.2596-1 G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.2596-1 G>A as a pathogenic variant.
Invitae RCV000813032 SCV000953365 likely pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2018-08-07 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 22) of the CLCN1 gene. While this 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, ExAC 0.02%). This variant has been observed to segregate with myotonia congenita in a family (PMID: 17932099) and has been reported in an individual with myotonia congenita (Invitae). ClinVar contains an entry for this variant (Variation ID: 449534). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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