Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000200289 | SCV000253767 | pathogenic | Charcot-Marie-Tooth Neuropathy X | 2024-01-24 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 102 of the GJB1 protein (p.Glu102Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with X-linked Charcot-Marie-Tooth disease (CMT) (PMID: 8004109, 14627639, 17353473, 25614874). ClinVar contains an entry for this variant (Variation ID: 216038). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GJB1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 9354338, 9469571, 9592087, 14627639). For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000349313 | SCV000329359 | pathogenic | not provided | 2022-10-05 | 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 (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9354338, 22771394, 25614874, 8004109, 9592087, 8737658, 17353473, 14627639, 9469571, 31827005, 11835375, 10873293) |
| Athena Diagnostics Inc | RCV000349313 | SCV000613484 | pathogenic | not provided | 2023-05-18 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. This variant has frequently been reported to result in a milder phenotype in patients when compared to complete loss-of-function variants (PMID: 8737658, 14627639, 27228968). In some published literature, this variant is referred to as 367A>G. Assessment of experimental evidence suggests this variant results in abnormal protein function. In functional studies, this variant formed channels, but these displayed abnormal voltage gating and dysfunction during acidification (consistent with the milder phenotype reported), as well as lower myelinated fiber density (PMID: 9592087, 14627639). |
| Mayo Clinic Laboratories, |
RCV000349313 | SCV001715661 | pathogenic | not provided | 2019-06-09 | criteria provided, single submitter | clinical testing | PS3, PS4, PP5 |
| Ambry Genetics | RCV002444807 | SCV002754074 | likely pathogenic | Inborn genetic diseases | 2020-06-16 | criteria provided, single submitter | clinical testing | The p.E102G variant (also known as c.305A>G), located in coding exon 1 of the GJB1 gene, results from an A to G substitution at nucleotide position 305. The glutamic acid at codon 102 is replaced by glycine, an amino acid with similar properties. This variant has been reported in multiple unrelated individuals affected with X-linked Charcot-Marie-Tooth disease (CMT) and was confirmed de novo in one individual as well as shown to segregate with the disease in another family (Abrams CK et al. J. Neurosci., 2003 Nov;23:10548-58; Boerkoel CF et al. Ann. Neurol., 2002 Feb;51:190-201; Ionasescu V et al. Hum. Mol. Genet., 1994 Feb;3:355-8; Ionasescu VV. Cell Biol. Int., 1998 Nov;22:807-13; Sahenk Z et al. J. Neurosci. Res., 1998 Jan;51:174-84). Experimental studies have shown that nerve xenografts from the patients with E102G showed altered Schwann cell membrane composition/organization, leading to axonal abnormalities (Sahenk Z et al. J. Neurosci. Res., 1998 Jan;51:174-84). Moreover, studies using Xenopus oocytes showed that this variant increased sensitivity of channels to intracellular acidification, affecting junctional conductance (Abrams CK et al. J. Neurosci., 2003 Nov;23:10548-58; Oh S et al. Neuron, 1997 Oct;19:927-38; Ressot C et al. J. Neurosci., 1998 Jun;18:4063-75). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| ARUP Laboratories, |
RCV003633486 | SCV004563416 | pathogenic | Charcot-Marie-Tooth disease X-linked dominant 1 | 2023-03-28 | criteria provided, single submitter | clinical testing | The GJB1 c.305A>G; p.Glu102Gly variant (rs779696968) is described in the literature in individuals and families with Charcot-Marie-Tooth (CMT) and is reported as a frequently detected variant in individuals with CMT (Cortese 2020, DiVincenzo 2014, Ionasescu 1994). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 216038) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The amino acid at this position is highly conserved computational analyses predict that this variant is deleterious (REVEL: 0.877). In support of this prediction, functional studies show this variant alters the voltage-gating, resulting in increased sensitivity to intracellular acidification (Abrams 2003, Ressot 1998). Based on available information, this variant is classified as pathogenic. References: Abrams CK et al Pathogenesis of X-linked Charcot-Marie-Tooth disease: differential effects of two mutations in connexin 32. J Neurosci. 2003 Nov 19;23(33):10548-58. PMID: 14627639. Cortese A et al. Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease. Neurology. 2020 Jan 7;94(1):e51-e61. PMID: 31827005. DiVincenzo C et al. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2014 Nov;2(6):522-9. PMID: 25614874. Ionasescu V et al. Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy. Hum Mol Genet. 1994 Feb;3(2):355-8. 8004109. Ressot C et al. Connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease show two distinct behaviors: loss of function and altered gating properties. J Neurosci. 1998 Jun 1;18(11):4063-75. PMID: 9592087 |
| Inherited Neuropathy Consortium | RCV000790300 | SCV000929706 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |