Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000168077 | SCV000218731 | pathogenic | Charcot-Marie-Tooth Neuropathy X | 2023-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 142 of the GJB1 protein (p.Arg142Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CMT1X (PMID: 9361298, 10102421, 11571214). ClinVar contains an entry for this variant (Variation ID: 188174). 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 expected to disrupt GJB1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg142 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8004109, 9361298, 10207904, 10848620). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Genomic Research Center, |
RCV000714875 | SCV000845622 | likely pathogenic | Charcot-Marie-Tooth disease X-linked dominant 1 | 2018-08-07 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV000714875 | SCV001160486 | likely pathogenic | Charcot-Marie-Tooth disease X-linked dominant 1 | 2019-05-08 | criteria provided, single submitter | clinical testing | The GJB1 c.425G>A; p.Arg142Gln variant (rs786204123) is reported in the literature in several individuals and families affected with X-linked Charcot-Marie-Tooth (CMT) disease (Dubourg 2001, Ikegami 1998, Stojkovic 1999). In one family, which also exhibited sensorineural deafness, this variant was found in at least six affected individuals and was absent from two unaffected relatives, although it was also found in two individuals without symptoms who may have been too young to manifest with disease (Stojkovic 1999). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 142 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (p.Arg142Gly, p.Arg142Trp) have been reported in individuals with CMT and are considered disease-causing (Bergoffen 1993, Lorefice 2017, Yuan 2018). Based on available information, the p.Arg142Gln variant is considered to be likely pathogenic. References: Bergoffen J et al. Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science. 1993 Dec 24;262(5142):2039-42. Dubourg O et al. Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease. Brain. 2001 Oct;124(Pt 10):1958-67. Ikegami T et al. Four novel mutations of the connexin 32 gene in four Japanese families with Charcot-Marie-Tooth disease type 1. Am J Med Genet. 1998 Dec 4;80(4):352-5. Lorefice L et al. Charcot-Marie-Tooth disease: genetic subtypes in the Sardinian population. Neurol Sci. 2017 Jun;38(6):1019-1025. Stojkovic T et al. Sensorineural deafness in X-linked Charcot-Marie-Tooth disease with connexin 32 mutation (R142Q). Neurology. 1999 Mar 23;52(5):1010-4. Yuan JH et al. Genetic and phenotypic profile of 112 patients with X-linked Charcot-Marie-Tooth disease type 1. Eur J Neurol. 2018 Dec;25(12):1454-1461. |
| Gene |
RCV001657932 | SCV001874268 | pathogenic | not provided | 2022-05-02 | criteria provided, single submitter | clinical testing | Previously reported many times in association with CMTX1; some patients with R142Q also had deafness and central nervous system symptoms (Stojkovic et al., 1999; Dubourg et al., 2001; Kulkarni et al., 2015; Lu et al., 2017; Bone et al., 1997).; Published functional studies demonstrate that the R142Q variant alters the formation and structure of gap junction plaques (Abrams et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12542510, 30042657, 9856562, 28071741, 17603245, 11571214, 25745327, 28469099, 19259128, 27544631, 21291455, 28448691, 9361298, 29998508, 32376792, 31323543, 31220874, 31842800, 32903794, 30952033, 33314704, 10102421) |
| Ambry Genetics | RCV002515186 | SCV003656587 | likely pathogenic | Inborn genetic diseases | 2022-12-08 | criteria provided, single submitter | clinical testing | The c.425G>A (p.R142Q) alteration is located in exon 2 (coding exon 1) of the GJB1 gene. This alteration results from a G to A substitution at nucleotide position 425, causing the arginine (R) at amino acid position 142 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple unrelated individuals in the hemizygous and heterozygous state in mildly affected females with features consistent with Charcot-Marie-Tooth disease (Dubourg, 2001; Kim, 2012; Milley, 2016; Lu, 2017; Chen, 2019; Hardy, 2019; Tian, 2021; Volodarsky, 2021). In addition, this alteration was shown to segregate with disease in multiple individuals from two families who have clinical features consistent with Charcot-Marie-Tooth disease (Stojkovic, 1999; Liang, 2019). This amino acid position is highly conserved in available vertebrate species. Functional assays demonstrate reduced junctional conductance compared to controls in vitro (Abrams, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. |
| Inherited Neuropathy Consortium | RCV000789950 | SCV000929335 | uncertain significance | Charcot-Marie-Tooth disease | flagged submission | literature only |