ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.83T>C (p.Ile28Thr) (rs768834663)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235732 SCV000293445 likely pathogenic not provided 2016-12-21 criteria provided, single submitter clinical testing A published I28T variant that is likely pathogenic has been identified in the GJB1 gene. The I28T variant has beenreported previously in individuals with Charcot-Marie-Tooth neuropathy (CMT) (Bone et al., 1997; Nicholson et al.,1998). It was not observed in approximately 6,500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I28Tvariant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as theseresidues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where aminoacids with similar properties to Isoleucine are tolerated across species. It is predicted to occur within the firsttransmembrane domain of the GJB1 protein, and a different missense variant in the same codon (I28N) as well asmultiple missense variants in nearby residues have been reported in the Human Gene Mutation Database inassociation with CMT (Stenson et al., 2014), supporting the functional importance of this region of the protein. Insilico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant islikely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001203741 SCV001374917 uncertain significance Charcot-Marie-Tooth Neuropathy X 2019-09-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 28 of the GJB1 protein (p.Ile28Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with clinical features of Charcot-Marie-Tooth disease (PMID: 9818870). ClinVar contains an entry for this variant (Variation ID: 246094). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). This variant disrupts the p.Ile28 amino acid residue in GJB1. Other variant(s) that disrupt this residue (p.Ile28Asn) have been determined to be pathogenic (PMID: 9361298, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Inherited Neuropathy Consortium RCV000789177 SCV000928529 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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