ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.305A>G (p.Glu102Gly) (rs779696968)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
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.
GeneDx 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.