Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000493545 | SCV000582848 | likely pathogenic | not provided | 2017-05-22 | criteria provided, single submitter | clinical testing | A variant that is likely pathogenic has been identified in the GJB1 gene. The S50P variant has been previously reported in two families with a clinical diagnosis of axonal CMT (Latour et al., 1997). The S50P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S50P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (S49P/Y, F51L, C53S/Y) have been reported in the Human Gene Mutation Database in association with CMT (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded |
| Athena Diagnostics | RCV000518090 | SCV000613477 | uncertain significance | not specified | 2016-12-02 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001856974 | SCV002184184 | uncertain significance | Charcot-Marie-Tooth Neuropathy X | 2021-04-20 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 10732813). ClinVar contains an entry for this variant (Variation ID: 430122). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 50 of the GJB1 protein (p.Ser50Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. |
| Inherited Neuropathy Consortium | RCV000789248 | SCV000928600 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |