ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.83T>A (p.Ile28Asn) (rs768834663)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198281 SCV000253677 pathogenic Charcot-Marie-Tooth Neuropathy X 2016-04-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 28 of the GJB1 protein (p.Ile28Asn). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is present in population databases (rs768834663, ExAC 0.002%). This variant has been reported in the literature in an individual affected with CMT1X (PMID: 9361298) . This variant has also been observed at Invitae in individuals affected with CMT1X. ClinVar contains an entry for this variant (Variation ID: 215983). A likely pathogenic missense variant is found at this codon and multiple missense mutations have been reported in adjacent codons (PMID: 9818870, 21309765, 15006706), which suggests that the Ile28 amino acid and its surrounding region is critical for protein function. Experiments testing the impact of the Ile28Asn missense change have not been reported. In summary, this is a rare missense change that has been observed in affected individuals and is located in a mutation rich region of the GJB1 protein. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756204 SCV000883940 likely pathogenic Charcot-Marie-Tooth Neuropathy X Type 1 2019-02-15 criteria provided, single submitter clinical testing The GJB1 p.Ile28Asn variant (rs768834663) was reported in a cohort of patients with CMT from Athena diagnostics (Bone, 1997). Among the 130 variants reported in this cohort, several affecting the same codon (c.83T>C; p.Ile28T) or nearby residues (p.Ser26Leu, p.Val27Ala and p.Ile30Asn) were observed in affected patients. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.0005 percent (identified on 1 out of 183,311 chromosomes), and reported to ClinVar as a pathogenic variant (Variation ID: 215983). The isoleucine at position 28 is highly conserved across the vertebrates and located in a transmembrane domain. Computational analyses of the p.Ile28Asn variant on protein structure and function indicates a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Based on these observations, the p.Ile28Asn variant is likely to be pathogenic. References: Bone et al. Connexin32 and X-linked Charcot-Marie-Tooth disease. Neurobiol Dis. 1997;4(3-4):221-30.
Molecular Genetics Laboratory,London Health Sciences Centre RCV000789176 SCV001336653 likely pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000789176 SCV000928528 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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