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12 Dec 2025	Monogenic hearing loss v5.49	GJB6	Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: GJB6. Tag Q2_25_expert_review was removed from gene: GJB6. Tag Q2_25_ NHS_review was removed from gene: GJB6.
12 Dec 2025	Monogenic hearing loss v5.49	GJB6	Ida Ertmanska reviewed gene: GJB6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
12 Dec 2025	Monogenic hearing loss v5.48	GJB6	Ida Ertmanska Source Expert Review Green was added to GJB6. Source NHS GMS was added to GJB6. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
23 May 2025	Monogenic hearing loss v5.8	GJB6	Eleanor Williams changed review comment from: Since this gene was last reviewed in 2020 there are have been two reports of the same variant in the gene associated with hearing loss in unrelated families. PMID: 40369851 - Elmakhzen et al 2025 - reports a 3rd case with of individuals carrying the same missense variant (ENST00000647029.1 (GJB6): c.175G>A (p.(Gly59Arg)) and syndromic hearing loss identified through WGS. The patient, a 13 year old girl, who presented with both congenital hearing loss and ectodermal anomalies. Both her grandfather and one maternal uncle showed congenital bilateral deafness (no genetic analysis). However the variant was found to be de novo in this proband with neither parent carrying the variant. The variant is absent from Gnomad 4.1.0. Duzkale et al 2022 - https://mednexus.org/doi/full/10.1097/JD9.0000000000000231 (not in PubMed). report a Turkish girl with nonsyndromic Hearing loss with p. Gly59Arg heterozygous missense mutation in the GJB6 gene. The variant was identified through panel sequencing of 75 genes from the PanelApp hearing loss panel, including GJB6. The variant was also present heterozygously in the mother and grandfather, who both had hearing loss and palmoplantar hyperkeratosis. The p.Gly59Arg mutation of GJB6 was first described in 2009 in a 32-year-old Japanese woman with mild palmoplantar keratoderma, knuckle pads, and severe sensorineural HL (PMID: 19416251).; to: Since this gene was last reviewed in 2020 there are have been two reports of the same variant in the gene associated with hearing loss in unrelated families. PMID: 40369851 - Elmakhzen et al 2025 - reports a 3rd case with of individuals carrying the same missense variant (ENST00000647029.1 (GJB6): c.175G>A (p.(Gly59Arg)) and bilateral syndromic hearing loss identified through WGS. The patient, a 13 year old girl, who presented with both congenital hearing loss and ectodermal anomalies. Both her grandfather and one maternal uncle showed congenital bilateral deafness (no genetic analysis). However the variant was found to be de novo in this proband with neither parent carrying the variant. The variant is absent from Gnomad 4.1.0. Duzkale et al 2022 - https://mednexus.org/doi/full/10.1097/JD9.0000000000000231 (not in PubMed). report a Turkish girl with nonsyndromic bilateral hearing loss with p. Gly59Arg heterozygous missense mutation in the GJB6 gene. The variant was identified through panel sequencing of 75 genes from the PanelApp hearing loss panel, including GJB6. The variant was also present heterozygously in the mother and grandfather, who both had hearing loss and palmoplantar hyperkeratosis. The p.Gly59Arg mutation of GJB6 was first described in 2009 in a 32-year-old Japanese woman with mild palmoplantar keratoderma, knuckle pads, and severe sensorineural HL (PMID: 19416251).
23 May 2025	Monogenic hearing loss v5.8	GJB6	Eleanor Williams commented on gene: GJB6: Since this gene was last reviewed in 2020 there are have been two reports of the same variant in the gene associated with hearing loss in unrelated families. PMID: 40369851 - Elmakhzen et al 2025 - reports a 3rd case with of individuals carrying the same missense variant (ENST00000647029.1 (GJB6): c.175G>A (p.(Gly59Arg)) and syndromic hearing loss identified through WGS. The patient, a 13 year old girl, who presented with both congenital hearing loss and ectodermal anomalies. Both her grandfather and one maternal uncle showed congenital bilateral deafness (no genetic analysis). However the variant was found to be de novo in this proband with neither parent carrying the variant. The variant is absent from Gnomad 4.1.0. Duzkale et al 2022 - https://mednexus.org/doi/full/10.1097/JD9.0000000000000231 (not in PubMed). report a Turkish girl with nonsyndromic Hearing loss with p. Gly59Arg heterozygous missense mutation in the GJB6 gene. The variant was identified through panel sequencing of 75 genes from the PanelApp hearing loss panel, including GJB6. The variant was also present heterozygously in the mother and grandfather, who both had hearing loss and palmoplantar hyperkeratosis. The p.Gly59Arg mutation of GJB6 was first described in 2009 in a 32-year-old Japanese woman with mild palmoplantar keratoderma, knuckle pads, and severe sensorineural HL (PMID: 19416251).
23 May 2025	Monogenic hearing loss v5.8	GJB6	Eleanor Williams Phenotypes for gene: GJB6 were changed from Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977; Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977 to Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977
19 May 2025	Monogenic hearing loss v5.7	GJB6	Sarah Leigh Tag cnv tag was added to gene: GJB6. Tag Q2_25_ promote_green tag was added to gene: GJB6. Tag Q2_25_expert_review tag was added to gene: GJB6. Tag Q2_25_ NHS_review tag was added to gene: GJB6.
19 May 2025	Monogenic hearing loss v5.7	GJB6	Sarah Leigh Phenotypes for gene: GJB6 were changed from hearing loss; Deafness, autosomal dominant 3B, 612643; Deafness, autosomal recessive 1B, 612645; Deafness, digenic GJB2/GJB6, 220290; Ectodermal dysplasia 2, Clouston type, 129500; Nonsyndromic Hearing Loss, Dominant to Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977; Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977
19 May 2025	Monogenic hearing loss v5.6	GJB6	Sarah Leigh Publications for gene: GJB6 were set to 10471490; 11896458; 11807148; 15150777; 24522190; 29921236; 39498320; 19416251; 40369851
19 May 2025	Monogenic hearing loss v5.5	GJB6	Sarah Leigh reviewed gene: GJB6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 1B, OMIM:612645, autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977, Deafness, autosomal recessive 1B, OMIM:612645, autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
19 May 2025	Monogenic hearing loss v5.5	GJB6	Sarah Leigh Publications for gene: GJB6 were set to 10471490; 24522190; 39498320; 19416251; 40369851
19 May 2025	Monogenic hearing loss v5.4	GJB6	Sarah Leigh Publications for gene: GJB6 were set to PMID:10471490; 10570462; 10610709; 11017065; 11807148; 11874494; 11896458; 12419304; 12490528; 12668604; 14571368; 15150777; 15213106; 15638823; 15994881; 17041943; 18324688; 20858605; 8663509; 9139825; 9799458
12 Jan 2021	Monogenic hearing loss v2.144	GJB3	Eleanor Williams changed review comment from: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen. A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in most cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535). 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in cell Monoallelic cases: PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER). PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss. PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects. PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene. PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed. PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed. PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant. PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31. PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed. PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype. PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr. Biallelic cases: PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del. Functional studies: PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WTCx31.; to: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen. A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in most cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535). 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in to the cell surface in a similar way to wild type protein. Monoallelic cases: PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER). PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss. PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects. PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene. PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed. PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed. PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant. PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31. PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed. PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype. PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr. Biallelic cases: PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del. Functional studies: PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WT Cx31.
12 Jan 2021	Monogenic hearing loss v2.144	GJB3	Eleanor Williams changed review comment from: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen. A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in many cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535) . 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in cell Monoallelic cases: PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER). PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss. PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects. PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene. PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed. PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed. PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant. PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31. PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed. PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype. PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr. Biallelic cases: PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del. Functional studies: PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WTCx31.; to: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen. A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in most cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535). 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in cell Monoallelic cases: PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER). PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss. PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects. PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene. PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed. PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed. PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant. PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31. PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed. PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype. PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr. Biallelic cases: PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del. Functional studies: PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WTCx31.
22 Dec 2020	Monogenic hearing loss v2.139	GJB6	Eleanor Williams commented on gene: GJB6: As reviewer Zornitza Stark reports this gene has Refuted status in association with hearing loss by ClinGen. However, leaving as amber, as there is still some evidence to support the possibility that SNV in this gene are associated with hearing loss (Grifa et al and Amritkumar et al).
02 Jan 2020	Monogenic hearing loss v2.4	GJB6	Zornitza Stark reviewed gene: GJB6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
12 Jun 2019	Monogenic hearing loss v1.114	GJB6	Eleanor Williams Classified gene: GJB6 as Amber List (moderate evidence)
12 Jun 2019	Monogenic hearing loss v1.114	GJB6	Eleanor Williams Added comment: Comment on list classification: After consideration by the Genomics England rare disease clinical team it was decided to rate this gene Amber until there is further evidence for the role of SNVs in this gene causing hearing loss.
12 Jun 2019	Monogenic hearing loss v1.114	GJB6	Eleanor Williams Gene: gjb6 has been classified as Amber List (Moderate Evidence).
27 Feb 2019	Monogenic hearing loss v1.102	GJB6	Eleanor Williams commented on gene: GJB6
17 Feb 2019	Monogenic hearing loss v1.59	GJB6	Emma Ashton reviewed gene: GJB6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: