ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.283G>A (p.Val95Met) (rs104894821)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168221 SCV000218889 pathogenic Charcot-Marie-Tooth Neuropathy X 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 95 of the GJB1 protein (p.Val95Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This sequence change has been reported in multiple patients and families affected with X-linked Charcot-Marie-Tooth (CMT) disease (PMID: 21254193, 10873293, 10586261, 16922730). In one large family, this change co-segregates with disease in six affected individuals (PMID: 21254193). ClinVar contains an entry for this variant (Variation ID: 10441). This missense change has been shown to interfere with the function of the GJB1 protein, also known as connexin 32. Studies in Xenopus oocytes found that this missense change prevents the formation of functional connexin 32 channels (PMID: 9592087). In mouse N2A neuroblastoma cells, this variant was found to disrupt gap junctions, leading to low conductance (PMID: 21254193). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000235924 SCV000292561 pathogenic not provided 2017-07-05 criteria provided, single submitter clinical testing The V95M missense pathogenic variant in the GJB1 gene has been reported previously in association with CMTX1 (Bone et al., 1995; IPNMDB database). Functional studies show that V95M prevents the formation of functional channels (Ressot et al., 1998; Wang et al., 2004). The V95M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, the V95M variant alters a highly conserved position in the protein, and other missense variants associated with CMTX1 have been reported in adjacent amino acids (H94Q/R/D/Y, A96P).
Athena Diagnostics Inc RCV000235924 SCV000841715 pathogenic not provided 2016-03-24 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000235924 SCV001245764 pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000011186 SCV001474497 pathogenic Charcot-Marie-Tooth Neuropathy X Type 1 2019-09-13 criteria provided, single submitter clinical testing The GJB1 c.283G>A; p.Val95Met variant (rs104894821) is reported in the literature in multiple individuals affected with X-linked Charcot-Marie-Tooth disease (Bone 1995, Kim 2017, Nam 2016, Montenegro 2011). This variant is reported in ClinVar (Variation ID: 10441), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 95 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show a significant defect in channel formation and function (Ressot 1998, Wang 2004). Based on available information, this variant is considered to be pathogenic. References: Bone LJ et al. New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease. Neurology. 1995 Oct;45(10):1863-6. Kim JK et al. X-linked Charcot-Marie-Tooth disease with GJB1 mutation presenting as acute disseminated encephalomyelitis-like illness: A case report. Medicine (Baltimore). 2017 Dec;96(49):e9176. Montenegro G et al. Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family. Ann Neurol. 2011 Mar;69(3):464-70. Nam SH et al. Identification of Genetic Causes of Inherited Peripheral Neuropathies by Targeted Gene Panel Sequencing. Mol Cells. 2016 May 31;39(5):382-8. 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. Wang HL et al. Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease. Neurobiol Dis. 2004 Mar;15(2):361-70.
OMIM RCV000011186 SCV000031413 pathogenic Charcot-Marie-Tooth Neuropathy X Type 1 2012-02-01 no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV000789817 SCV000929201 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.