Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000216227 | SCV000279581 | likely pathogenic | not provided | 2017-06-23 | criteria provided, single submitter | clinical testing | The K124N variant in the GJB1 gene has been reported previously in association with X-linked Charcot-Marie-Tooth disease (CMTX) (Bone et al., 1997). The K124N variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K124N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Lysine are tolerated across species and is predicted to be within the intracellular loop between the second and third transmembrane regions of the GJB1 protein (Bone et al., 1997; Kleopa et al., 2012). Multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with GJB1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. This variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Invitae | RCV001294422 | SCV001483300 | uncertain significance | Charcot-Marie-Tooth Neuropathy X | 2023-10-14 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 124 of the GJB1 protein (p.Lys124Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of X-linked Charcot-Marie-Tooth disease (PMID: 9361298; Invitae). ClinVar contains an entry for this variant (Variation ID: 234611). 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 not expected to disrupt GJB1 protein function. This variant disrupts the p.Lys124 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 27234031), which suggests that this may be a clinically significant amino acid residue. 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. |
| Inherited Neuropathy Consortium | RCV000789170 | SCV000928522 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |