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Monogenic hearing loss v5.36 RIPOR2 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotypes accessed on 21st October 2025
Monogenic hearing loss v5.36 RIPOR2 Eleanor Williams 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
Monogenic hearing loss v5.35 RIPOR2 Arina Puzriakova changed review comment from: PMID: 37864412 - 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.; to: 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.
Monogenic hearing loss v5.35 RIPOR2 Arina Puzriakova Tag watchlist tag was added to gene: RIPOR2.
Monogenic hearing loss v5.35 RIPOR2 Arina Puzriakova Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v5.34 RIPOR2 Arina Puzriakova Classified gene: RIPOR2 as Amber List (moderate evidence)
Monogenic hearing loss v5.34 RIPOR2 Arina Puzriakova Added comment: 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.
Monogenic hearing loss v5.34 RIPOR2 Arina Puzriakova Gene: ripor2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.33 RIPOR2 Arina Puzriakova edited their review of gene: RIPOR2: Changed rating: AMBER
Monogenic hearing loss v5.33 RIPOR2 Arina Puzriakova edited their review of gene: RIPOR2: Changed publications to: 24958875, 32631815, 37864412; Changed phenotypes to: Deafness, autosomal dominant 21, OMIM:607017, Deafness, autosomal recessive 104, OMIM:616515; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v5.33 RIPOR2 Arina Puzriakova edited their review of gene: RIPOR2: Added comment: PMID: 37864412 - 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.; Changed phenotypes to: Deafness, autosomal recessive 104, OMIM:616515
Monogenic hearing loss v4.31 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v4.31 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v4.31 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v4.31 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v4.31 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v4.30 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v4.30 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051
Monogenic hearing loss v4.29 RIPOR2 Achchuthan Shanmugasundram 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
Monogenic hearing loss v4.29 RIPOR2 Achchuthan Shanmugasundram 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
Monogenic hearing loss v4.28 RIPOR2 Achchuthan Shanmugasundram Classified gene: RIPOR2 as Amber List (moderate evidence)
Monogenic hearing loss v4.28 RIPOR2 Achchuthan Shanmugasundram Added comment: 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.
Monogenic hearing loss v4.28 RIPOR2 Achchuthan Shanmugasundram Gene: ripor2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v4.27 RIPOR2 Achchuthan Shanmugasundram changed review comment from: 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.

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.; to: 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.
Monogenic hearing loss v4.27 RIPOR2 Achchuthan Shanmugasundram edited their review of gene: RIPOR2: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v4.27 RIPOR2 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: RIPOR2.
Monogenic hearing loss v4.27 RIPOR2 Achchuthan Shanmugasundram reviewed gene: RIPOR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 24958875, 32631815; Phenotypes: Deafness, autosomal dominant 21, OMIM:607017, ?Deafness, autosomal recessive 104, OMIM:616515; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v4.25 RIPOR2 Dmitrijs Rots reviewed gene: RIPOR2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32631815; Phenotypes: Adult-onset hearing loss; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.233 RIPOR2 Eleanor Williams 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
Monogenic hearing loss v2.221 RIPOR2 Eleanor Williams commented on gene: RIPOR2
Monogenic hearing loss v2.220 RIPOR2 Eleanor Williams Source Expert list was added to RIPOR2.
Monogenic hearing loss v2.44 RIPOR2 Arina Puzriakova Added comment: Comment on mode of inheritance: Only two publications, describing different patterns of inheritance (AR or AD).
Monogenic hearing loss v2.44 RIPOR2 Arina Puzriakova Mode of inheritance for gene: RIPOR2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.43 RIPOR2 Arina Puzriakova Classified gene: RIPOR2 as Amber List (moderate evidence)
Monogenic hearing loss v2.43 RIPOR2 Arina Puzriakova Added comment: Comment on list classification: Recent publication described several families, but with a founder variant. Therefore currently still insufficient cases for a rating upgrade.
Monogenic hearing loss v2.43 RIPOR2 Arina Puzriakova Gene: ripor2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.42 RIPOR2 Arina Puzriakova reviewed gene: RIPOR2: Rating: ; Mode of pathogenicity: None; Publications: 32631815; Phenotypes: Sensorineural hearing loss; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v1.56 RIPOR2 Anna de Burca reviewed gene: RIPOR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 24958875, 27269051, 30280293; Phenotypes: Sensorineural hearing loss; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal