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| Clefting v6.17 | PRKCI |
Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants. Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort). Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? Functional evidence: 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). ; to: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants. Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); lower lip pits + hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? Functional evidence: 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). |
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| Clefting v6.17 | PRKCI |
Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants. Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort). Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). ; to: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants. Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort). Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? Functional evidence: 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). |
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| Clefting v6.17 | PRKCI |
Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants). Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not LoF intolerant! pLI score for this gene = 0.01 - not predicted to be loss-of-function intolerant. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). ; to: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants. Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort). Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). |
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| Clefting v6.17 | PRKCI |
Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts and peridermopathies. Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by trio WGS. Vairant c.1148A>G (p.Asn383Ser) was found de novo in five unrelated individuals, indicating a hotspot mutation. 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). Sources: Other; to: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants). Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not LoF intolerant! pLI score for this gene = 0.01 - not predicted to be loss-of-function intolerant. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). |
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| Clefting v6.16 | PRKCI |
Ida Ertmanska gene: PRKCI was added gene: PRKCI was added to Clefting. Sources: Other Q4_25_promote_green tags were added to gene: PRKCI. Mode of inheritance for gene: PRKCI was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRKCI were set to 40902599 Phenotypes for gene: PRKCI were set to van der Woude syndrome, MONDO:0019508 Review for gene: PRKCI was set to GREEN Added comment: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts and peridermopathies. Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by trio WGS. Vairant c.1148A>G (p.Asn383Ser) was found de novo in five unrelated individuals, indicating a hotspot mutation. 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). Sources: Other |
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| Clefting | IRF6 | Helen Brittain reviewed IRF6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting | IRF6 | Ellen McDonagh marked IRF6 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting | IRF6 | Ellen McDonagh classified IRF6 as green | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting | IRF6 | Ellen McDonagh commented on IRF6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting | IRF6 | Ellen McDonagh classified IRF6 as green | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting | IRF6 | Usha Kini reviewed IRF6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||