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

dbSNP: rs768834663

Total submissions: 4

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203741	SCV001374917	uncertain significance	Charcot-Marie-Tooth Neuropathy X	2019-09-28	criteria provided, single submitter	clinical testing	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. 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 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). This variant is not present in population databases (ExAC no frequency). 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. 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.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783768	SCV005397779	likely pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2024-06-07	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (T>C) at position 83 of the coding sequence of the GJB1 gene that results in an isoleucine to threonine amino acid change at residue 28 of the gap junction protein beta 1 protein. This residue falls within the connexin domain of the protein (UniProt). This is a previously reported variant (ClinVar 246094) that has been observed in families affected by X-linked Charcot-Marie-Tooth neuropathy (PMID: 9361298, 9818870). Other variants that disrupt this residue have been determined to be pathogenic (PMID: 9361298, ClinVar). This variant is absent from the gnomAD v4.1.0 population database (0/~1211000 alleles). Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Ile28 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been performed, to our knowledge. Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PM5, PP2, PP3
Inherited Neuropathy Consortium	RCV000789177	SCV000928529	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only