ClinVar Miner

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

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Total submissions: 5
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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.
GeneDx 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, Mayo Clinic 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

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