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| Monogenic hearing loss v6.33 | COL4A6 | Ida Ertmanska Mode of inheritance for gene: COL4A6 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.32 | COL4A6 | Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated male individuals reported in literature with hemizygous COL4A6 variants and non-syndromic hearing loss. Hence, this gene can be promoted to Green at the next update. MOI should be set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as little segregation evidence is provided for the families - unclear if female carriers may also present with deafness.; to: Comment on list classification: There are more than 3 unrelated male individuals reported in literature with hemizygous COL4A6 variants and non-syndromic hearing loss. Hence, this gene can be promoted to Green at the next update. MOI should be set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as little segregation evidence is provided for the families - unclear if female carriers may also present with COL4A6-related deafness. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.32 | COL4A6 | Ida Ertmanska commented on gene: COL4A6: Comment on list classification: There are more than 3 unrelated male individuals reported in literature with hemizygous COL4A6 variants and non-syndromic hearing loss. Hence, this gene can be promoted to Green at the next update. MOI should be set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as little segregation evidence is provided for the families - unclear if female carriers may also present with deafness. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.32 | COL4A6 | Ida Ertmanska edited their review of gene: COL4A6: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.32 | COL4A6 |
Ida Ertmanska changed review comment from: PMID: 41092388 Owrang et al., 2026 Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease. PMID: 40928595 Jagannath et al., 2025 Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). PMID: 39272213 Feng et al., 2024 Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S. PMID: 33840813 O'Brien et al., 2022 Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15. Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss. Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). The association between COL4A6 and hearing loss, X-linked 6 was classified as Limited in ClinGen (Feb 2022, Hearing Loss GCEP).; to: PMID: 41092388 Owrang et al., 2026 Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease. PMID: 40928595 Jagannath et al., 2025 Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). Parents unaffected, not genotyped. PMID: 39272213 Feng et al., 2024 Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S. PMID: 33840813 O'Brien et al., 2022 Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15. Both variants were inherited from heterozygous affected mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss. Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). The association between COL4A6 and hearing loss, X-linked 6 was classified as Limited in ClinGen (Feb 2022, Hearing Loss GCEP). |
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| Monogenic hearing loss v6.32 | COL4A6 | Ida Ertmanska Phenotypes for gene: COL4A6 were changed from Deafness, X-linked 6, OMIM:300914 to ?Deafness, X-linked 6 , OMIM:300914; hearing loss, X-linked 6, MONDO:0010484 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.31 | COL4A6 | Ida Ertmanska Publications for gene: COL4A6 were set to PMID: 23714752; 7592929; 7711741; 7972123; 8125972; 8175748; 8356449; 8661006; 9463311 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.30 | COL4A6 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: COL4A6. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.30 | COL4A6 |
Ida Ertmanska changed review comment from: PMID: 41092388 Owrang et al., 2026 Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease. PMID: 40928595 Jagannath et al., 2025 Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). PMID: 39272213 Feng et al., 2024 Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S. PMID: 33840813 O'Brien et al., 2022 Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15. Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss. Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026).; to: PMID: 41092388 Owrang et al., 2026 Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease. PMID: 40928595 Jagannath et al., 2025 Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). PMID: 39272213 Feng et al., 2024 Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S. PMID: 33840813 O'Brien et al., 2022 Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15. Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss. Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). The association between COL4A6 and hearing loss, X-linked 6 was classified as Limited in ClinGen (Feb 2022, Hearing Loss GCEP). |
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| Monogenic hearing loss v6.30 | COL4A6 |
Ida Ertmanska changed review comment from: PMID: 41092388 Owrang et al., 2026 Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease. PMID: 40928595 Jagannath et al., 2025 Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). PMID: 39272213 Feng et al., 2024 Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S. PMID: 33840813 O'Brien et al., 2022 Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951 + 1 G > T leads to skipping of exon 15. Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 varinats in the two kindreds, which are also likely to contribute to hearing loss. The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026).; to: PMID: 41092388 Owrang et al., 2026 Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease. PMID: 40928595 Jagannath et al., 2025 Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). PMID: 39272213 Feng et al., 2024 Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S. PMID: 33840813 O'Brien et al., 2022 Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15. Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss. Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). |
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| Monogenic hearing loss v6.30 | COL4A6 | Ida Ertmanska reviewed gene: COL4A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 33840813, 39272213, 40928595, 41092388; Phenotypes: ?Deafness, X-linked 6 , OMIM:300914, hearing loss, X-linked 6, MONDO:0010484; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v2.227 | COL4A6 | Eleanor Williams Tag for-review was removed from gene: COL4A6. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v2.227 | COL4A6 | Eleanor Williams Phenotypes for gene: COL4A6 were changed from #300914:?Deafness, X-linked 6; diffuse leiomyomatosis with Alport syndrome = contiguous gene with COL4A5; Leiomyomatosis, diffuse, with Alport syndrome, 308940 (4) to Deafness, X-linked 6, OMIM:300914 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v2.221 | COL4A6 | Eleanor Williams commented on gene: COL4A6: The rating of this gene has been updated following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v2.220 | COL4A6 |
Eleanor Williams Source Expert Review Amber was added to COL4A6. Rating Changed from Green List (high evidence) to Amber List (moderate evidence) |
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| Monogenic hearing loss v2.21 | COL4A6 | Eleanor Williams Tag for-review tag was added to gene: COL4A6. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v2.4 | COL4A6 | Eleanor Williams edited their review of gene: COL4A6: Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v2.4 | COL4A6 |
Eleanor Williams changed review comment from: Provisionally associated with ?Deafness, X-linked 6 #300914 (XLR) in OMIM. Only 1 family reported in PMID: 23714752 - Rost et al 2014 - a Hungarian three-generation family with X-linked nonsyndromic congenital hearing loss with a missense mutation (c.1771G>A, p.Gly591Ser) in COL4A6 in all affected family members. In situ hybridization and immunostaining demonstrated expression of the COL4A6 homologs in the otic vesicle of the zebrafish and in the murine inner ear, supporting its role in normal ear development and function. Pubmed search didn’t find any other cases.; to: Provisionally associated with ?Deafness, X-linked 6 #300914 (XLR) in OMIM. Only 1 family reported in PMID: 23714752 - Rost et al 2014 - a Hungarian three-generation family with X-linked nonsyndromic congenital hearing loss with a missense mutation (c.1771G>A, p.Gly591Ser) in COL4A6 in all affected family members. In situ hybridization and immunostaining demonstrated expression of the COL4A6 homologs in the otic vesicle of the zebrafish and in the murine inner ear, supporting its role in normal ear development and function. Pubmed search didn’t find any other cases. |
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| Monogenic hearing loss v2.4 | COL4A6 | Eleanor Williams commented on gene: COL4A6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v2.4 | COL4A6 | Zornitza Stark reviewed gene: COL4A6: Rating: RED; Mode of pathogenicity: None; Publications: 23714752; Phenotypes: Deafness, X-linked 6, MIM#300914; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||