ClinVar Miner

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

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Total submissions: 6
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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
OMIM RCV000011186 SCV000031413 pathogenic X-linked hereditary motor and sensory neuropathy 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

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