Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000200289 | SCV000253767 | pathogenic | Charcot-Marie-Tooth Neuropathy X | 2019-12-03 | 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 | 2018-08-30 | criteria provided, single submitter | clinical testing | The E102G missense variant in the GJB1 gene has been reported previously in association with CMTX1 (Ionasescu et al.,1994; Ionasescu,1998; Boerkoel et al., 2002). In a study of 17000 individuals with neuropathy, the E102G variant accounted for 2.5% of pathogenic variants in the cohort (DiVincenzo et al., 2014). Functional studies show that E102G alters the voltage dependence of the channel, affecting its ability to function properly (Ressot et al., 1998). The E102G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, E102G is interpreted to be a pathogenic variant. |
| 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. |
| Inherited Neuropathy Consortium | RCV000790300 | SCV000929706 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |