Activity
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| DDG2P v8.2 | FRYL |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Julie Evans and detailed in my review below, there is only evidence available from a single publication to support the gene-disease association. The limitations listed including variability of phenotypes, large number of LoF variants in gnomAD 4.1.1 and the evidence from drosophila model not translating to humans due to humans having two paralogs suggest that this gene should not be rated amber. However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Note that it was previously agreed with the G2P team and the NHSE that all genes with G2P classification of moderate and abiove should be rated green on this panel. Hence, the rating should stay green, pending updates from G2P.; to: Comment on list classification: As reviewed by Julie Evans and detailed in my review below, there is evidence available from only a single publication to support the gene-disease association. The limitations listed including variability of phenotypes, large number of LoF variants in gnomAD 4.1.1 and the evidence from drosophila model not translating to humans due to humans having two paralogs suggest that this gene should not be rated green. However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Note that it was previously agreed with the G2P team and the NHSE that all genes with G2P classification of 'moderate' and above should be rated green on this panel. Hence, the rating should stay green, pending updates from G2P. |
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| DDG2P v8.2 | FRYL | Achchuthan Shanmugasundram Classified gene: FRYL as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v8.2 | FRYL |
Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Julie Evans and detailed in my review below, there is only evidence available from a single publication to support the gene-disease association. The limitations listed including variability of phenotypes, large number of LoF variants in gnomAD 4.1.1 and the evidence from drosophila model not translating to humans due to humans having two paralogs suggest that this gene should not be rated amber. However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Note that it was previously agreed with the G2P team and the NHSE that all genes with G2P classification of moderate and abiove should be rated green on this panel. Hence, the rating should stay green, pending updates from G2P. |
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| 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 Added comment: Comment on phenotypes: OMIM phenotype added 20 Mar 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v6.16 | 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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