Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000200289 | SCV000253767 | pathogenic | Charcot-Marie-Tooth Neuropathy X | 2020-07-27 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid with glycine at codon 102 of the GJB1 protein (p.Glu102Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (ExAC 0.02%). This variant has been reported in multiple individuals affected with X-linked Charcot-Marie-Tooth disease (CMT) (PMID: 8004109, 14627639, 17353473). A study of a large cohort of individuals with neuropathy found that this variant accounted for 2.5% of pathogenic CMT variants (PMID: 25614874). ClinVar contains an entry for this variant (Variation ID: 216038). Experimental studies have shown that this missense change alters the voltage-gating properties of the channel encoded by GJB1, making it more sensitive to intracellular acidification (PMID: 9354338, 9592087). In addition, xenografts of Schwann cells expressing this variant led to altered myelinated fiber density in a mouse model system (PMID: 9469571, 14627639). For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000349313 | SCV000329359 | pathogenic | not provided | 2020-12-23 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect (homotypic channels differ from wild type in sensitivity and time course; impairs modulatory function of Schwann cells on axons, resulting in profound cytoskeletal alterations leading to distal axonal degeneration) (Ressot et al., 1998; Sahenk et al., 1998); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 14627639, 17353473, 9354338, 11835375, 22771394, 10873293, 25614874, 8004109, 8737658, 31827005, 9592087, 9469571) |
| Athena Diagnostics Inc | RCV000349313 | SCV000613484 | pathogenic | not provided | 2019-02-05 | criteria provided, single submitter | clinical testing | The best available variant frequency is uninformative because there are too few occurrences in population data. Statistically enriched in patients compared to ethnically matched controls. Co-occurs with otherwise positive results less than expected. Damaging to protein function(s) relevant to disease mechanism. |
| Mayo Clinic Laboratories, |
RCV000349313 | SCV001715661 | pathogenic | not provided | 2019-06-09 | criteria provided, single submitter | clinical testing | PS3, PS4, PP5 |
| Inherited Neuropathy Consortium | RCV000790300 | SCV000929706 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |