ClinVar Genomic variation as it relates to human health

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.

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; Invitae). 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.

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)

PVS1, PS4_moderate, PM2, PP1

This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been seen in multiple individuals with apparently autosomal recessive myotonia congenita both internally and in the literature (PMID: 21387378). However, it has also been reported in individuals with possible autosomal dominant myotonia congenita (PMID: 23417379, 26036855). Computational tools yielded predictions that this variant may interfere with normal RNA splicing.