ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.425G>A (p.Arg142Gln) (rs786204123)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168077 SCV000218731 pathogenic Charcot-Marie-Tooth Neuropathy X 2020-09-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 142 of the GJB1 protein (p.Arg142Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with CMT1X and has been observed to co-segregate with disease in an affected family (PMID: 9361298, 11571214, 10102421). ClinVar contains an entry for this variant (Variation ID: 188174). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Arg142Trp) has been determined to be pathogenic (PMID: 8004109, 9361298, 10207904, 10848620). This suggests that the arginine residue is critical for GJB1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000714874 SCV000845621 uncertain significance D-2-hydroxyglutaric aciduria 1 2018-08-07 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000714875 SCV000845622 likely pathogenic Charcot-Marie-Tooth Neuropathy X Type 1 2018-08-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000714875 SCV001160486 likely pathogenic Charcot-Marie-Tooth Neuropathy X Type 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.
GeneDx RCV001657932 SCV001874268 pathogenic not provided 2021-08-06 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); The majority of missense variants in this gene are considered pathogenic; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30952033, 32903794, 31323543, 31842800, 31220874, 32376792, 30042657, 29998508, 9361298, 28448691, 21291455, 27544631, 19259128, 28469099, 25745327, 11571214, 10102421, 12542510, 17603245, 28071741, 9856562)
Inherited Neuropathy Consortium RCV000789950 SCV000929335 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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