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| Optic neuropathy v6.43 | 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, 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. PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026). The gene is Amber on the Optic atrophy panel in PanelApp Australia, and it has not been curated in ClinGen.; 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. PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026). The gene is Amber on the Optic atrophy panel in PanelApp Australia, and it has not been curated in ClinGen or Gene2Phenotype. |
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| Optic neuropathy v6.43 | 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, 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. PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026).; 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. PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026). The gene is Amber on the Optic atrophy panel in PanelApp Australia, and it has not been curated in ClinGen. |
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| Optic neuropathy v6.43 | 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. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update. However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - possibly variant specific phenotype?; 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. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update. However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - possibly a variant-specific phenotype. |
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| Optic neuropathy v6.43 | 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. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update. However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - variant specific phenotype?; 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. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update. However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - possibly variant specific phenotype? |
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| Optic neuropathy v6.43 | 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. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update. However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. 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).; 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. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update. However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - variant specific phenotype? |
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| Optic neuropathy v6.43 | 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, 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. ; 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. PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026). |
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| Optic neuropathy v6.43 | PPIB |
Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: PPIB. Tag Q2_26_expert_review tag was added to gene: PPIB. |
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| Optic neuropathy v6.43 | 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. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update. However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. 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).; 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. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update. However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. 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). |
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| Optic neuropathy v6.43 | 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-disease association is ambiguous and should be rated as Amber.; 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. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update. However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. 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). |
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| Optic neuropathy v6.43 | PPIB | Ida Ertmanska edited their review of gene: PPIB: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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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