ClinVar Genomic variation as it relates to human health

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 163 of the CHRNE protein (p.Ser163Leu). This variant is present in population databases (rs121909516, gnomAD 0.05%). This missense change has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 8755487). 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. This variant is also known as S143L. ClinVar contains an entry for this variant (Variation ID: 18360). 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 CHRNE protein function. Experimental studies have shown that this missense change affects CHRNE function (PMID: 8755487). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Published functional studies demonstrate a damaging effect with failure of protein product to assemble with the alpha subunit of the acetylcholine receptor (PMID: 8755487); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.S143L; This variant is associated with the following publications: (PMID: 32403337, 33199334, 37091313, 8755487)

The CHRNE c.488C>T variant is predicted to result in the amino acid substitution p.Ser163Leu. This variant has previously been reported in the compound heterozygous state in two siblings with autosomal recessive fast-channel congenital myasthenic syndrome 4B, and functional studies support its pathogenicity (Ohno et al. 1996. PubMed: 8755487, reported as S143L). It is documented in an additional affected individual from a neuromuscular disorders patient cohort; however, zygosity of this variant and patient phenotype were not defined (Gonzalez-Quereda L et al 2020. PubMed ID: 32403337). This variant is reported in 0.047% of alleles in individuals of European (non-Finnish) descent in gnomAD, and the majority of ClinVar entries indicate this variant is likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/18360/evidence/). This variant is interpreted as likely pathogenic.

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.

The CHRNE p.S163L variant was identified in the literature in two compound heterozygous siblings with congenital myasthenic syndrome (Ohno_1996_PMID:8755487). The variant was identified in dbSNP (ID: rs121909516) and ClinVar (classified as uncertain significance by Invitae and Illumina; as likely pathogenic by GeneDx and Baylor Genetics; and as pathogenic by OMIM). The variant was identified in control databases in 74 of 281378 chromosomes at a frequency of 0.0002630, and was observed at the highest frequency in the European (non-Finnish) population in 60 of 127756 chromosomes (freq: 0.0004696) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.S163 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional analysis of the p.S163L variant demonstrates reduced protein expression compared to wildtype and impaired acetylcholine receptor subunit assembly (Ohno_1996_PMID:8755487). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome, Splice AI genome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.