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| Optic neuropathy v5.26 | PPIB |
Ida Ertmanska changed review comment from: PMID: 41045073 Valentin et al., 2025 (journal pre-proof) Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families. In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease. The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals. PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, no homozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher). PMID: 21282188 Pyott et al., 2011 3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB. Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous. Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each. Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped. Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected. ; to: PMID: 41045073 Valentin et al., 2025 (journal pre-proof) Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families. In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease. The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals. PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher). PMID: 21282188 Pyott et al., 2011 3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB. Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous. Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each. Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped. Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected. |
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| Optic neuropathy v5.26 | PPIB |
Ida Ertmanska changed review comment from: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. As 8/9 families are of European (Austrian) origins, a founder variant effect cannot be excluded. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188). Based on the available evidence, this gene should be rated Amber for Optic neuropathy.; to: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. As 8/9 families are of European (Austrian) origins, a founder variant effect cannot be excluded. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188). Based on the available evidence, this gene-disease association is ambiguous and should be rated as Amber. |
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| Optic neuropathy v5.26 | PPIB |
Ida Ertmanska commented on gene: PPIB: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. As 8/9 families are of European (Austrian) origins, a founder variant effect cannot be excluded. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188). Based on the available evidence, this gene should be rated Amber for Optic neuropathy. |
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| Optic neuropathy v5.26 | PPIB |
Ida Ertmanska changed review comment from: PMID: 41045073 Valentin et al., 2025 (journal pre-proof) Authors report 19 individuals from 9 families (8 Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families. In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease. The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals. PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, no homozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher). PMID: 21282188 Pyott et al., 2011 3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB. Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous. Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each. Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped. Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected. Sources: Other; to: PMID: 41045073 Valentin et al., 2025 (journal pre-proof) Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families. In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease. The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals. PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, no homozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher). PMID: 21282188 Pyott et al., 2011 3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB. Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous. Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each. Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped. Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected. |
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| Optic neuropathy v5.26 | PPIB | Ida Ertmanska Classified gene: PPIB as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v5.26 | PPIB | Ida Ertmanska Gene: ppib has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v5.25 | PPIB |
Ida Ertmanska gene: PPIB was added gene: PPIB was added to Optic neuropathy. Sources: Other Mode of inheritance for gene: PPIB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PPIB were set to 21282188; 41045073 Phenotypes for gene: PPIB were set to optic atrophy, MONDO:0003608 Review for gene: PPIB was set to AMBER Added comment: PMID: 41045073 Valentin et al., 2025 (journal pre-proof) Authors report 19 individuals from 9 families (8 Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families. In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease. The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals. PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, no homozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher). PMID: 21282188 Pyott et al., 2011 3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB. Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous. Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each. Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped. Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected. Sources: Other |
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