Monogenic hearing loss
Gene: RIPOR2
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
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
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
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
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Sensorineural hearing loss
Publications
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
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.
Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051
Phenotypes for gene: RIPOR2 were changed from Deafness, autosomal dominant 21, OMIM:607017; ?Deafness, autosomal recessive 104, OMIM:616515 to Deafness, autosomal dominant 21, OMIM:607017; ?Deafness, autosomal recessive 104, OMIM:616515
Phenotypes for gene: RIPOR2 were changed from ?Deafness, autosomal recessive 104 , OMIM:616515 to Deafness, autosomal dominant 21, OMIM:607017; ?Deafness, autosomal recessive 104, OMIM:616515
Gene: ripor2 has been classified as Amber List (Moderate Evidence).
Tag founder-effect tag was added to gene: RIPOR2.
Phenotypes for gene: RIPOR2 were changed from Hearing loss, non-syndromic, autosomal recessive (Diaz-Horta (2014) Proc Natl AcadSci USA 111,9864); Sensorineural hearing loss; OrphaNet: ORPHA90636; OMIM:616515 to ?Deafness, autosomal recessive 104 , OMIM:616515
Source Expert list was added to RIPOR2.
Mode of inheritance for gene: RIPOR2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Gene: ripor2 has been classified as Amber List (Moderate Evidence).
FAM65B was changed to RIPOR2
new-gene-name was removed from FAM65B. Panel: Congenital hearing impairment (profound/severe)
This gene has been classified as Amber List (Moderate Evidence).
This gene has been classified as Amber List (Moderate Evidence).
Phenotypes for FAM65B were set to Hearing loss, non-syndromic, autosomal recessive (Diaz-Horta (2014) Proc Natl AcadSci USA 111,9864);Sensorineural hearing loss;OrphaNet: ORPHA90636;OMIM:616515
Mode of inheritance for FAM65B was changed to BIALLELIC, autosomal or pseudoautosomal
Publications for FAM65B were set to 17150207; 24958875; 9055809; 9205841;24958875;27269051
FAM65B was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Radboud University Medical Center, Nijmegen