Monogenic hearing loss

Gene: RIPOR2

I don't know

Comment on list classification: Only one variant was reported with both monoallelic and biallelic inheritance. There is some functional data for both modes of inheritance. Although there are 12 unrelated cases reported with the same monoallelic variant, this variant was suggested to be founder variant. Hence, this gene can only be rated amber with the current evidence for both modes of inheritance.

Created: 10 Apr 2024, 10:12 a.m. | Last Modified: 10 Apr 2024, 10:12 a.m.

Panel Version: 4.28

Biallelic variants:
PMID:24958875 reported six affected members from a single Turkish family with a homozygous splice site variant in the RIPOR2 gene (c.102-1G-A) and with deafness. In addition, morpholino knockdown of the orthologous gene in zebrafish embryos resulted in a significant reduction in the number of saccular hair cells and neuromasts, and caused hearing loss.

Monoallelic variants:
PMID:32631815 reported a heterozygous 12 nucleotide in-frame deletion (c.1696_1707del, p.Gln566_Lys569del) in RIPOR2 that was detected in 12 families of Dutch origin with non-syndromic hearing loss.

In total, the variant was detected in 59/63 affected participants, but also in five unaffected subjects from three family. Age of onset was highly variable, from congenital to 70 years (mean age: 30.6 years) - unaffected family members who harboured the variant were aged 23, 40, 49, 50, and 51 years, respectively. The authors speculated that the four affected subjects without the variant represent phenocopies. The presence of an identical variant in 12 families of common origin, as well as haplotype analysis, indicates a founder effect. Hence, the 'founder-effect' tag was added.

Functional analysis of this variant showed aberrant localisation of RIPOR2 variant protein in early postnatal mouse hair cells, ex vivo; and failure to rescue the stereocilia defects of Ripor2 knockout mice, in contrast to the rescue effect observed in cells expressing wild-type RIPOR2.

Created: 10 Apr 2024, 10:02 a.m. | Last Modified: 10 Apr 2024, 10:08 a.m.

Panel Version: 4.27

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Deafness, autosomal dominant 21, OMIM:607017; ?Deafness, autosomal recessive 104, OMIM:616515

Publications

• 24958875
• 32631815

Green List (high evidence)

Enough evidence for the green rating, at least for the monoallelic inheritance. ClinGen supports evidence of this gene for the green rating.

Created: 9 Mar 2024, 9:11 a.m. | Last Modified: 9 Mar 2024, 9:11 a.m.

Panel Version: 4.25

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Adult-onset hearing loss

Publications

• PMID: 32631815

Comment on phenotypes: OMIM phenotypes accessed on 21st October 2025

Created: 21 Oct 2025, 12:10 p.m. | Last Modified: 21 Oct 2025, 12:10 p.m.

Panel Version: 5.36

The mode of inheritance 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

I don't know

Comment on list classification: There are now 2 unrelated consanguineous families with biallelic variants and 12 families with the same monoallelic founder variant in this gene linked to hearing loss (PMIDs: 24958875; 32631815; 37864412). The presence of unaffected carriers calls into question the penetrance of heterozygous variants. Animal studies have yielded variable results.

ClinGen have classified the association with autosomal recessive nonsyndromic genetic hearing loss as Strong, and autosomal dominant nonsyndromic hearing loss as Limited (both last assessed on 15-05-2024).

Overall the evidence is still borderline and therefore this gene should remain Amber.

Created: 21 Oct 2025, 11:22 a.m. | Last Modified: 21 Oct 2025, 11:22 a.m.

Panel Version: 5.34

PMID: 37864412 (2023) - a distinct homozygous LOF variant (c.1561C>T (p.Arg521*)) in exon 14 of the RIPOR2 gene was identified by WES in three siblings from a consanguineous Tunisian family with non-syndromic bilateral profound hearing and vestibular dysfunctions. Parents were unaffected heterozygous carriers. No other variants in hearing loss genes were found. Zebrafish model with a stop codon inserted within ripor2 exon 14 showed that F2 larva did not exhibit a different hearing or balance behaviour compared to wild-type.

Created: 21 Oct 2025, 11:08 a.m. | Last Modified: 21 Oct 2025, 11:24 a.m.

Panel Version: 5.35

Comment on mode of inheritance: Only two publications, describing different patterns of inheritance (AR or AD).

Created: 1 Sep 2020, 3:59 p.m. | Last Modified: 1 Sep 2020, 3:59 p.m.

Panel Version: 2.44

Comment on list classification: Recent publication described several families, but with a founder variant. Therefore currently still insufficient cases for a rating upgrade.

Created: 1 Sep 2020, 3:55 p.m. | Last Modified: 1 Sep 2020, 3:55 p.m.

Panel Version: 2.43

PMID: 32631815 (2020) - A heterozygous 12 nucleotide in-frame deletion (c.1696_1707del, p.Gln566_Lys569del) in RIPOR2 was detected in 12 families of Dutch origin with non-syndromic hearing loss.

In total, the variant was detected in 59/63 affected participants, but also in five unaffected subjects from three family. Age of onset was highly variable, from congenital to 70 years (mean age: 30.6 years) - unaffected family members who harboured the variant were aged 23, 40, 49, 50, and 51 years, respectively. The authors speculate that the four affected subjects without the variant represent phenocopies. The presence of an identical variant in 12 families of common origin, as well as haplotype analysis, indicates a founder effect.

Functional analysis of the variant showed aberrant localisation of mutant-RIPOR2 in early postnatal mouse hair cells, ex vivo; and failure to rescue the stereocilia defects of Ripor2 knockout mice, in contrast to the rescue effect observed in cells expressing wild-type RIPOR2.

Created: 1 Sep 2020, 3:51 p.m. | Last Modified: 1 Sep 2020, 3:51 p.m.

Panel Version: 2.42

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Deafness, autosomal dominant 21, OMIM:607017; Deafness, autosomal recessive 104, OMIM:616515

Publications

• 24958875
• 32631815
• 37864412

I don't know

PMID:24958875 used whole exome sequencing to identify a variant in RIPOR2 (formerly known as FAM65B) affecting a canonical splice site. RNA studies demonstrated skipping of exon 3 as a result of the variant. The homozygous variant segregated with hearing loss in six members of a consanguineous Turkish family with prelingual hearing loss. This remains the only case reported as pathogenic or likely pathogenic in ClinVar. PMID:27269051 and 30280293 report functional evidence for the role of RIPOR2 in the development of stereocilia, including evidence that mouse knockouts are deaf.

Created: 12 Feb 2019, 2:07 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Sensorineural hearing loss

Publications

• 24958875
• 27269051
• 30280293

Added new-gene-name tag. New HGNC-approved name for this gene is RIPOR2.

Created: 14 Sep 2017, 10:04 a.m.

Comment on list classification: A single variant reported in a large consanguinous Turkish family. In vitro evidence and animal model. ClinGen group have rated this strong evidence, however based on the PanelApp guidelines this gene does not reach green evidence level, and so rated amber until evidence in additional unrelated cases arises.

Created: 25 Jul 2017, 11:10 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
#616515:?Deafness, autosomal recessive 104[Deafness, sensorineural, profound]

Publications

• PMID:17150207
• 24958875
• 9055809
• 9205841