Monogenic hearing loss

Gene: CLIC5

Green List (high evidence)

Comment on list classification: There are now more than 3 unrelated families reported in literature with biallelic CLIC5 variants and non-syndromic hearing loss. Hence, this gene should be promoted to Green at the next update.

Created: 11 May 2026, 1 p.m. | Last Modified: 11 May 2026, 1 p.m.

Panel Version: 6.2

ADDITIONAL CASES SINCE 2019:

PMID: 40957967 Pshennikova et al., 2026
Founder variant in Eastern Siberia: CLIC5 c.644 G>A p.(Trp215*) causes progressive AR deafness. Found in homozygous state in 22 patients from 16 unrelated families in Siberia (Russia). Hearing loss was sensorineural, symmetrical and variable by severity (from moderate to profound). Founder calculated to have arisen 78 generations ago. Method: WES + Sanger.

PMID: 40928595 Jagannath et al., 2025
Cohort of 105 Indian individuals with hearing loss. Family 19 - proband with congenital bilateral severe-to-profound sensorineural hearing loss, homozygous for variant (CLIC5):c.401A > G, (p.Asn134Ser) - only 1 het individual in gnomAD v4.1.1. Heterozygous family members unaffected. Method: Exome seq + Sanger. *Assessed to be VUS by ACMG criteria in the article.

PMID: 33114113 Wonkam-Tingang et al., 2020
Report of a Cameroonian family with non-syndromic hearing impairment and biallelic CLIC5 variants NM_016929.5:c.224T>C; p.(L75P) and NM_016929.5: c.63+1G>A. The variants segregated with disease, with 3 affected family members carrying both variants, and other individuals being unaffected if WT or carrying one of the mutations. The 3 affected sibs were 25-36 years old, no age of onset given.

Created: 11 May 2026, 12:59 p.m. | Last Modified: 11 May 2026, 1:05 p.m.

Panel Version: 6.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Deafness, autosomal recessive 103, OMIM:616042

Publications

• 33114113
• 40928595
• 40957967

Comment on list classification: Downgrading the rating from green to amber as upon review there was only 1 case, plus some functional data from mouse.

Created: 9 Jul 2019, 9:11 a.m. | Last Modified: 9 Jul 2019, 9:11 a.m.

Panel Version: 1.117

Checking with the Genomics England clinical team about the rating of this gene.

Created: 10 Apr 2019, 2:37 p.m.

This gene has a provisional association with ?Deafness, autosomal recessive 103 (616042) in OMIM.

PMID: 30575790 - Geng et al 2018 - Characterized a loss-of-function mutant mouse model (miR-183CGT/GT), in which the miR-183/96/182 cluster gene is inactivated by a gene-trap (GT) construct. The homozygous mutant mice show profound congenital hearing loss with severe defects in cochlear hair cell (HC) maturation, alignment, hair bundle formation and the checkboard-like pattern of the cochlear sensory epithelia. Several predicted target genes of the miR-183/96/182 cluster that are known to play important roles in HC development and function, including Clic5, Rdx, Ezr, Rac1, Myo1c, Pvrl3 and Sox2, are upregulated in the cochlea.

PMID: 24781754 - Seco et al 2015 - 2 sibs, born of consanguineous Turkish parents, with early-onset autosomal recessive deafness-103 with a homozygous truncating mutation in the CLIC5 gene. The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. Screening for mutations in the CLIC5 gene in over 200 mostly Dutch or Spanish probands with hearing impairment did not identify any other mutations.

PMID: 24285636 Salles et al 2014 - Further work on the Jitterbug mouse model - Confocal and scanning electron microscopy of CLIC5-deficient jitterbug (jbg) mice revealed progressive fusion of stereocilia as early as postnatal day 10. Radixin (RDX), protein tyrosine phosphatase receptor Q (PTPRQ), and taperin (TPRN), deafness-associated proteins that also concentrate at the base of stereocilia, were mislocalized in fused stereocilia of jbg mice.

PMID: 17021174 - Gagnon et al 2006 - From OMIM: 'Jitterbug' (jbg/jbg) mutant mouse is an autosomal recessive phenotype characterized by overt head-bobbing and circling behavior with an inability to swim, indicating vestibular dysfunction. Mutant mice also show hearing loss that progresses to complete deafness. Linkage analysis and candidate gene analysis identified the cause of the phenotype as a homozygous intragenic deletion in the Clic5 gene that resulted in a truncated protein.

Only 1 family plus some functional data from mouse.

Created: 10 Apr 2019, 2:10 p.m.

I don't know

I don't think this association was replicated in humans yet and original family is small - the gene also only scores 7 on a recently published rating schema so only just makes it into "moderate" category - see https://search.clinicalgenome.org/kb/gene-validity/9545

So query whether evidence is sufficient for a green rating in PanelApp?

Created: 22 Mar 2019, 1:35 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Nonsyndromic sensorineural deafness

Publications

• PMID: 24781754
• 17021174

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
#616042:?Deafness, autosomal recessive 103[Hearing loss, sensorineuralDownsloping audiogramVestibular areflexiaVestibular dysfunction]

Publications

• PMID:10793131
• 17021174
• 18028448
• 24781754

Comment on list classification: Good evidence from OMIM and expert

Created: 1 Feb 2016, 4:53 p.m.

Green List (high evidence)

Would want to report a Tier 1 variant

Created: 19 Oct 2015, 6:22 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal