Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001995761 | SCV002275022 | likely pathogenic | Congenital myasthenic syndrome 4A | 2021-05-26 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Asp195 amino acid residue in CHRNE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12356851). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt CHRNE protein function. This variant has not been reported in the literature in individuals with CHRNE-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 195 of the CHRNE protein (p.Asp195Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. |
| Neuberg Centre For Genomic Medicine, |
RCV003388621 | SCV004100634 | uncertain significance | Congenital myasthenic syndrome 4B | criteria provided, single submitter | clinical testing | The missense variant p.D195Y in CHRNE (NM_000080.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.D195Y variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between aspartic acid and tyrosine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.D195Y missense variant is predicted to be damaging by both SIFT and PolyPhen2. The aspartic acid residue at codon 195 of CHRNE is conserved in all mammalian species. The nucleotide c.583 in CHRNE is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. |