Submissions for variant NM_000083.3(CLCN1):c.774+1G>A

gnomAD frequency: 0.00002  dbSNP: rs776073429

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254934	SCV000322641	pathogenic	not provided	2024-04-25	criteria provided, single submitter	clinical testing	Identified, in the heterozygous and compound heterozygous state, in multiple unrelated patients with myotonia referred for testing at GeneDx and in published literature (PMID: 26036855, 23417379, 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: 26036855, 29606556, 21387378, 23417379, 22094069, 23739125, 17932099, 34529042)
Illumina Laboratory Services, Illumina	RCV000305146	SCV000467111	pathogenic	Batten-Turner congenital myopathy	2017-04-28	criteria provided, single submitter	clinical testing	The CLCN1 c.774+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. Across three studies this variant was identified in a total of eight individuals. Tan et al. (2011) found the c.774+1G>A variant in a compound heterozygous state with another splice variant in an individual with myotonia congenita. The c.774+1G>A variant was subsequently found in a heterozygous state in a 31 year old man with myotonia as well as his affected mother (Hehir et al. 2013). Additionally, Bissay et al. (2015) identified the variant in at least five members of a family with both Brugada syndrome and myotonic features. The c.774+1G>A variant segregated with disease within the family. Control data are unavailable from these studies but the c.774+1G>A variant is reported at a frequency of 0.00019 in the African population of the Exome Aggregation Consortium, though this frequency is based on only two alleles in a region of good sequencing coverage. Based on the evidence from the literature and the potential impact of splice donor variants, the c.774+1G>A variant is classified as pathogenic for myotonia congenita. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543122	SCV000636299	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-09-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 of the CLCN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CLCN1 are known to be pathogenic (PMID: 17932099, 22094069, 23739125). This variant is present in population databases (rs776073429, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with autosomal recessive myotonia congenita (PMID: 21387378, 34529042; internal data). ClinVar contains an entry for this variant (Variation ID: 265646). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000254934	SCV001715970	pathogenic	not provided	2020-02-17	criteria provided, single submitter	clinical testing	PVS1, PS4_moderate, PM2, PP1
Revvity Omics, Revvity	RCV000254934	SCV002017362	pathogenic	not provided	2021-10-07	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000254934	SCV002771122	pathogenic	not provided	2024-01-24	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 statistically more frequent in the patient population than in the general population. 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 has been seen in multiple individuals with apparently autosomal recessive myotonia congenita (PMID: 21387378). However, it has also been reported in individuals with possible autosomal dominant myotonia congenita (PMID: 23417379, 26036855).
Fulgent Genetics, Fulgent Genetics	RCV000543122	SCV005667218	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-04-10	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV005250044	SCV005900418	pathogenic	Congenital myotonia, autosomal recessive form	2024-12-06	criteria provided, single submitter	clinical testing	This sequence change in CLCN1 occurs within the canonical splice donor site of intron 6. It is predicted to cause skipping of biologically relevant exon 6/23, resulting in an in-frame deletion (removes amino acids 233-258) that is expected to escape nonsense-mediated decay. Exon 6 corresponds to the transmembrane F helix and the proximal part of the F-G loop, which is a critical region (PMID: 37892996). The highest population minor allele frequency in the population database gnomAD v4.1 is 0.004% (3/74,786 alleles) in the Africa/African American population. This variant has been detected as compound heterozygous in at least three individuals with myotonia congenita (PMID: 21387378, 29606556; Royal Melbourne Hospital). At least one individual with this variant had a clinical diagnosis of myotonia congenita, which is highly specific for CLCN1-related disease. Affected heterozygotes have been reported with a milder phenotype, and the variant appears to segregate with disease in these families (PMID: 26036855, 23417379). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Strong, PM2_Supporting, PM3_Supporting, PP1, PP4_Strong