ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31130284, 31544778, 32660787, 21221019, 24037712, 25065301, 32117024, 26510092, 23933576, 24349310, 27614575, 29606556, 28403181, 28427807, 23739125, 8533761, 15786415, 22094069)

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 105 of the CLCN1 protein (p.Arg105Cys). This variant is present in population databases (rs201509501, gnomAD 0.2%). This variant has been observed in several individuals affected with myotonia congenita and is almost always reported with p.Phe167Leu (PMID: 23933576, 25065301, 21221019, 26510092, 8533761). In several individuals these two variants were reported along with a third CLCN1 variant (PMID: 22094069, 24349310, 24037712) and in at least three individuals p.Arg105Cys and p.Phe167Leu were determined to be on the same chromosome (in cis) (PMID: 23739125, 28427807, 32117024). ClinVar contains an entry for this variant (Variation ID: 639252). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN1 protein function. Experimental studies have shown that this missense change does not substantially affect CLCN1 function (PMID: 23933576, 26510092). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This sequence change in CLCN1 is predicted to replace arginine with cysteine at codon 105, p.(Arg105Cys). The arginine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in the cytoplasmic alpha-A helix (PMID: 33573884). There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.1% (53/44,826 alleles) in the East Asian population. This variant is typically reported in cis with c.501C>G p.(Phe167Leu) (PMID: 21221019, 21387378, 22094069, 22109722, 23739125, 24349310, 28427807, 33573884). It has been reported alone in the heterozygous state in individuals with inconsistent phenotypes or unaffected (PMID: 8533761, 28403181, 32660787), and compound heterozygous with a pathogenic variant in a foetus undergoing prenatal carrier testing (PMID: 31130284). Patch clamp assays in Xenopus oocytes and mammalian cell lines with limited validation demonstrate normal voltage-dependent activation for this variant (PMID: 23933576, 26510092, 34529042). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.772). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: BS3_Supporting, PP3.

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.