Activity
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21 actions
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| DDG2P v8.2 | FRYL | Achchuthan Shanmugasundram Classified gene: FRYL as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v8.2 | FRYL | Achchuthan Shanmugasundram Gene: fryl has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v8.1 | FRYL |
Achchuthan Shanmugasundram changed review comment from: PMID:38479391 (2024) reported 14 unrelated individuals with heterozygous FRYL variants (5 missense, 8 frameshift/stop-gain, 1 canonical splice) presenting with developmental delay/intellectual disability, dysmorphic features, and variable congenital anomalies across multiple systems. DD/ID was the only universal feature (14/14); all other phenotypes were variable and nonspecific, and 8/14 individuals harboured additional P/LP variants (in SF3B4, DHCR7, SLC6A19, SDHA) or VUSs in other genes that could partially confound phenotype attribution. Thirteen of 14 variants were confirmed de novo; the remaining variant (p.Ser2397Ile) was not confirmed de novo (duo testing could not exclude maternal inheritance), was present at low frequency in gnomAD, and showed no functional impact in Drosophila modelling — consistent with VUS rather than pathogenic classification. Of the 4/5 missense variants modelled using the fly fry ortholog, only 1 showed severe loss-of-function, 2 showed partial LoF, and 1 showed no effect, providing mixed functional support. Key concerns limiting confidence: (1) Half of the reported variants (7) are present in gnomAD v4.1.1. (2) gnomAD v4.1.1 shows numerous NMD-predicted variants distributed throughout FRYL, inconsistent with the proposed LoF-intolerance/ haploinsufficiency mechanism. (3) All the reported variants have an overall germline classification of 'Conflicting' or 'Uncertain significance' in ClinVar. (4) The fly model uses a single fry ortholog, whereas humans have two paralogs (FRY and FRYL), limiting translatability to human-specific FRYL disease (5) No familial segregation data exist (all cases simplex). (6) High rate of co-occurring candidate variants in other genes (8/14) confounds phenotype attribution. This gene has been associated with Pan-Chung-Bellen syndrome in OMIM (MIM #621049), which was last accessed on 02 September 2026. This gene is rated with 'moderate' rating on the DD panel of Gene2Phenotype, with amber rating on relevant panels in PanelApp Australia and has not been associated with any phenotypes in ClinGen. This gene is also rated amber on the Intellectual disability and Fetal anomalies panels in Genomics England PanelApp. Overall, this represents a single-publication gene-disease claim with substantive unresolved population genetics and functional modelling concerns — further independent case series and reconciliation with gnomAD v4 constraint data are needed before upgrading to green.; to: PMID:38479391 (2024) reported 14 unrelated individuals with heterozygous FRYL variants (5 missense, 8 frameshift/stop-gain, 1 canonical splice) presenting with developmental delay/intellectual disability, dysmorphic features, and variable congenital anomalies across multiple systems. DD/ID was the only universal feature (14/14); all other phenotypes were variable and nonspecific, and 8/14 individuals harboured additional P/LP variants (in SF3B4, DHCR7, SLC6A19, SDHA) or VUSs in other genes that could partially confound phenotype attribution. Thirteen of 14 variants were confirmed de novo; the remaining variant (p.Ser2397Ile) was not confirmed de novo (duo testing could not exclude maternal inheritance), was present at low frequency in gnomAD, and showed no functional impact in Drosophila modelling — consistent with VUS rather than pathogenic classification. Of the 4/5 missense variants modelled using the fly fry ortholog, only 1 showed severe loss-of-function, 2 showed partial LoF, and 1 showed no effect, providing mixed functional support. Key concerns limiting confidence: (1) Half of the reported variants (7) are present in gnomAD v4.1.1. (2) gnomAD v4.1.1 shows numerous NMD-predicted variants distributed throughout FRYL, inconsistent with the proposed LoF-intolerance/ haploinsufficiency mechanism. (3) All the reported variants have an overall germline classification of 'Conflicting' or 'Uncertain significance' in ClinVar. (4) The fly model uses a single fry ortholog, whereas humans have two paralogs (FRY and FRYL), limiting translatability to human-specific FRYL disease (5) No familial segregation data exist (all cases simplex). (6) High rate of co-occurring candidate variants in other genes (8/14) confounds phenotype attribution. This gene has been associated with Pan-Chung-Bellen syndrome in OMIM (MIM #621049), which was last accessed on 02 September 2026. This gene is rated with 'moderate' rating on the DD panel of Gene2Phenotype, with amber rating on relevant panels in PanelApp Australia and has not been associated with any phenotypes in ClinGen. This gene is also rated amber on the Intellectual disability and Fetal anomalies panels in Genomics England PanelApp. |
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| DDG2P v8.1 | FRYL | Achchuthan Shanmugasundram edited their review of gene: FRYL: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v8.1 | FRYL |
Achchuthan Shanmugasundram edited their review of gene: FRYL: Added comment: PMID:38479391 (2024) reported 14 unrelated individuals with heterozygous FRYL variants (5 missense, 8 frameshift/stop-gain, 1 canonical splice) presenting with developmental delay/intellectual disability, dysmorphic features, and variable congenital anomalies across multiple systems. DD/ID was the only universal feature (14/14); all other phenotypes were variable and nonspecific, and 8/14 individuals harboured additional P/LP variants (in SF3B4, DHCR7, SLC6A19, SDHA) or VUSs in other genes that could partially confound phenotype attribution. Thirteen of 14 variants were confirmed de novo; the remaining variant (p.Ser2397Ile) was not confirmed de novo (duo testing could not exclude maternal inheritance), was present at low frequency in gnomAD, and showed no functional impact in Drosophila modelling — consistent with VUS rather than pathogenic classification. Of the 4/5 missense variants modelled using the fly fry ortholog, only 1 showed severe loss-of-function, 2 showed partial LoF, and 1 showed no effect, providing mixed functional support. Key concerns limiting confidence: (1) Half of the reported variants (7) are present in gnomAD v4.1.1. (2) gnomAD v4.1.1 shows numerous NMD-predicted variants distributed throughout FRYL, inconsistent with the proposed LoF-intolerance/ haploinsufficiency mechanism. (3) All the reported variants have an overall germline classification of 'Conflicting' or 'Uncertain significance' in ClinVar. (4) The fly model uses a single fry ortholog, whereas humans have two paralogs (FRY and FRYL), limiting translatability to human-specific FRYL disease (5) No familial segregation data exist (all cases simplex). (6) High rate of co-occurring candidate variants in other genes (8/14) confounds phenotype attribution. This gene has been associated with Pan-Chung-Bellen syndrome in OMIM (MIM #621049), which was last accessed on 02 September 2026. This gene is rated with 'moderate' rating on the DD panel of Gene2Phenotype, with amber rating on relevant panels in PanelApp Australia and has not been associated with any phenotypes in ClinGen. This gene is also rated amber on the Intellectual disability and Fetal anomalies panels in Genomics England PanelApp. Overall, this represents a single-publication gene-disease claim with substantive unresolved population genetics and functional modelling concerns — further independent case series and reconciliation with gnomAD v4 constraint data are needed before upgrading to green.; Changed phenotypes to: Pan-Chung-Bellen syndrome, OMIM:621049, Pan-Chung-Bellen syndrome, MONDO:0975953, FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities |
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| DDG2P v8.1 | FRYL | Julie Evans reviewed gene: FRYL: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v6.440 | FRYL | Ida Ertmanska Tag gene-checked was removed from gene: FRYL. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v6.440 | FRYL | Ida Ertmanska Phenotypes for gene: FRYL were changed from Pan-Chung-Bellen syndrome, OMIM:621049; MONDO:0975953; FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities to Pan-Chung-Bellen syndrome, OMIM:621049; Pan-Chung-Bellen syndrome, MONDO:0975953 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v6.439 | FRYL | Ida Ertmanska Phenotypes for gene: FRYL were changed from MONDO:0975953; FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities to Pan-Chung-Bellen syndrome, OMIM:621049; MONDO:0975953; FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v6.438 | FRYL | Ida Ertmanska Tag gene-checked tag was added to gene: FRYL. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v6.17 | FRYL | Achchuthan Shanmugasundram reviewed gene: FRYL: Rating: GREEN; Mode of pathogenicity: ; Publications: 38479391; Phenotypes: MONDO:0975953, FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v6.17 | MED12 | Achchuthan Shanmugasundram edited their review of gene: MED12: Added comment: The DDG2P confidence category, allelic requirement and molecular mechanism for MED12-related Opitz-Kaveggia syndrome are definitive, monoallelic_X_hemizygous and undetermined (PMIDs: 17334363, 18973276, 20507344, 24039113, 26273451, 27081531, 27286923, 27312080). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00747. The DDG2P confidence category, allelic requirement and molecular mechanism for MED12-related Lujan-Fryns syndrome are definitive, monoallelic_X_hemizygous and undetermined (PMIDs: 17369503, 24123922, 24715367, 27286923, 27312080, 27500536, 27980443, 28544239, 30006928, 31536828, 6711603). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P00913. The DDG2P confidence category, allelic requirement and molecular mechanism for MED12-related developmental disorder are definitive, monoallelic_X_heterozygous and loss of function (PMIDs: 33244165, 33244166, 35385210). More details can be found in https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03071.; Changed publications to: 17369503, 35385210, 27980443, 18973276, 20507344, 27286923, 24039113, 30006928, 6711603, 27312080, 33244166, 27500536, 24715367, 24123922, 28544239, 33244165, 27081531, 17334363, 31536828, 26273451; Changed phenotypes to: OMIM:305450.0, LUJAN-FRYNS SYNDROME, OMIM:309520, OMIM:309520.0, OPITZ-KAVEGGIA SYNDROME, OMIM:305450, MED12-related Lujan-Fryns syndrome, MONDO:0700092, MED12-related developmental disorder, MED12-related Opitz-Kaveggia syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v6.16 | FRYL |
Achchuthan Shanmugasundram gene: FRYL was added gene: FRYL was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype Mode of inheritance for gene: FRYL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FRYL were set to 38479391 Phenotypes for gene: FRYL were set to MONDO:0975953; FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities |
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| DDG2P v5.32 | PCGF2 | Achchuthan Shanmugasundram Phenotypes for gene: PCGF2 were changed from INTELLECTUAL DUSBILITY; Craniofacial Neurological Cardiovascular and Skeletal Features to PCGF2-related craniofacial neurological cardiovascular and skeletal features (Turnpenny-Fry syndrome), OMIM:618371 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v5.31 | PCGF2 | Achchuthan Shanmugasundram edited their review of gene: PCGF2: Changed phenotypes to: PCGF2-related craniofacial neurological cardiovascular and skeletal features (Turnpenny-Fry syndrome), OMIM:618371 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v5.3 | PCGF2 | Achchuthan Shanmugasundram edited their review of gene: PCGF2: Added comment: The DDG2P confidence category for the disease PCGF2-related craniofacial neurological cardiovascular and skeletal features (Turnpenny-Fry syndrome), OMIM:618371 is strong. The allelic requirement and mutation consequence are monoallelic_autosomal and altered gene product structure (PMID: 30526864;34750959;36105049;30343942).; Changed publications to: 36105049, 34750959, 30343942, 30526864; Changed phenotypes to: Craniofacial Neurological Cardiovascular and Skeletal Features, INTELLECTUAL DISABILITY, PCGF2-related craniofacial neurological cardiovascular and skeletal features (Turnpenny-Fry syndrome), OMIM:618371 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v3.12 | MED12 | Achchuthan Shanmugasundram reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: ; Publications: 33244166, 31536828, 6711603, 17369503, 24123922, 17334363, 24715367, 28544239, 27980443, 27312080, 33244165, 30006928, 27286923, 27500536, 35385210; Phenotypes: LUJAN-FRYNS SYNDROME, OMIM:309520, OPITZ-KAVEGGIA SYNDROME, OMIM:305450, MED12-related developmental disorder; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v3.12 | FRY | Achchuthan Shanmugasundram reviewed gene: FRY: Rating: RED; Mode of pathogenicity: ; Publications: 21937992; Phenotypes: AUTOSOMAL RECESSIVE INTELLECTUAL DEVELOPMENTAL DISORDER; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v0.2 | FRY | Rebecca Foulger reviewed gene: FRY: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v0.1 | MED12 |
Rebecca Foulger Added phenotypes LUJAN-FRYNS SYNDROME 309520 for gene: MED12 Publications for gene MED12 were changed from 17334363 to 6711603 |
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| DDG2P v0.1 | FRY |
Rebecca Foulger gene: FRY was added gene: FRY was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype Mode of inheritance for gene: FRY was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FRY were set to 21937992 Phenotypes for gene: FRY were set to AUTOSOMAL RECESSIVE MENTAL RETARDATION |
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