ClinVar Genomic variation as it relates to human health

Observed with a pathogenic variant in a patient with myotonia congenita, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Brugnoni et al., 2013); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23113340, 25438602, 7581380, 9040760, 33263785, 31589614, 23739125, 7951215)

This variant is expected to result in the loss of a functional protein. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls and therefore is consistent with pathogenicity. This variant is primarily reported as autosomal recessive myotonia congenita (PMID: 17932099, 18337730, 23739125, 24349310), however, it has also been reported as autosomal dominant myotonia congenita (PMID: 23893571).

The CLCN1 c.1437_1450delACCCTGCGGAGGCT (p.Pro480HisfsTer24) variant results in a frameshift variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Pro480HisfsTer24 variant has been reported in at least 14 individuals with myotonia congenita (MC), which includes three in a homozygous state and six in a compound heterozygous state (Meyer-Kleine et al. 1994; Lehmann-Horn et al. 1995; Meyer-Kleine et al. 1995; Mailander et al. 1996; Fialho et al. 2007; Dupre et al. 2009; Raja Rayan et al. 2012; Brugnoni et al. 2013). The variant appears to be associated with an autosomal recessive inheritance pattern, as the majority of evaluated heterozygous family members were unaffected. However, a single clinically unaffected heterozygous male was reported to display latent myotonia (Mailander et al. 1996). Homozygosity for the variant also reportedly results in a more severe phenotype associated with transient weakness and severely reduced chloride conductance in muscle fibers, consistent with features of recessive MC. The p.Pro480HisfsTer24 variant was absent from at least 660 control chromosomes and is reported at a frequency of 0.000150 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Pro480HisfsTer24 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 variant was identified as compound heterozygous.

This sequence change creates a premature translational stop signal (p.Pro480Hisfs*24) in the CLCN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLCN1 are known to be pathogenic (PMID: 17932099, 22094069, 23739125). This variant is present in population databases (rs768119034, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive myotonia congenita (PMID: 7951215, 18337730, 22649220, 23739125, 24349310). This variant has been reported in individual(s) with autosomal dominant myotonia congenita (PMID: 7951215, 23893571); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 279778). For these reasons, this variant has been classified as Pathogenic.

The c.1437_1450del (p.(Pro480Hisfs*24)) variant was found in a heterozygous state in 3 Slovak patients with Myotonia congenita and in all of them also the second Likely Pathogenic variant was found: in two of them it was c.2680C>T (p.(Arg894*), whereas in the last one c.2364+2T>C splicing variant. The c.1437_1450del variant is listed as a disease-causing in the HGMD database (CD941645). GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.000121.

PM2_supporting: this variant is absent from gnomAD v4.0 (adequate coverage >20X confirmed). The highest population allele frequency in gnomAD v3.1.2 is 0.00016 (0.016%; 11/68038 alleles in European non-Finnish population). PM3_verystrong: this variant has been found in a compound heterozygous state in multiple individuals with AR myotonia congenital (>4 points). PVS1 met: frameshift variant predicted to undergo NMD. Exon is present in a biologically relevant transcript in a gene where LOF is a known mechanism of disease. PS4 met: this variant has been described in more than 10 unrelated probands with consistent phenotype for disorder. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.

CLCN1: PVS1, PM2, PS4:Moderate

Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.

Variant interpreted as Pathogenic and reported on 10-22-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.