Monogenic hearing loss

Gene: COL4A6

Green List (high evidence)

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.

Created: 22 Jul 2026, 2:47 p.m. | Last Modified: 22 Jul 2026, 2:47 p.m.

Panel Version: 6.32

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).

Created: 22 Jul 2026, 2:34 p.m. | Last Modified: 22 Jul 2026, 2:44 p.m.

Panel Version: 6.32

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
?Deafness, X-linked 6 , OMIM:300914; hearing loss, X-linked 6, MONDO:0010484

Publications

• 33840813
• 39272213
• 40928595
• 41092388

Red List (low evidence)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 1:19 p.m. | Last Modified: 3 Mar 2022, 1:19 p.m.

Panel Version: 2.221

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.

Created: 28 Jan 2020, 10:39 a.m. | Last Modified: 28 Jan 2020, 10:40 a.m.

Panel Version: 2.4

Red List (low evidence)

Out of all the papers listed here, only this one describes the association with deafness, based on a single family.

Created: 2 Jan 2020, 3:52 a.m. | Last Modified: 2 Jan 2020, 3:52 a.m.

Panel Version: 2.4

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Deafness, X-linked 6, MIM#300914

Publications

• 23714752

Green List (high evidence)

Comment on mode of inheritance: X-linked recessive = biallelic mutations in females.

Created: 17 Feb 2016, 12:57 p.m.

Inheritance:X-linked recessive

Created: 9 Feb 2016, 10:05 a.m.

Inheritance:X-linked recessive Inheritance:X-linked recessive

Created: 7 Feb 2016, 8:55 a.m.

Mode of inheritance
Other

Phenotypes
#300914:?Deafness, X-linked 6[Deafness, sensorineural, bilateralCochlear malformationIncomplete separation of the cochlea from the internal auditory canal]

Publications

• PMID:23714752
• 7592929
• 7711741
• 7972123
• 8125972
• 8175748
• 8356449
• 8661006
• 9463311

Comment on list classification: Good evidence from OMIM and expert review

Created: 31 Jan 2016, 8:05 a.m.