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

gnomAD frequency: 0.00003  dbSNP: rs771721648

Total submissions: 4

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	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-01-04	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; Invitae). 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 Inc	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.