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Intellectual disability v6.11 U2AF2 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: U2AF2.
Tag Q3_23_NHS_review was removed from gene: U2AF2.
Intellectual disability v6.11 U2AF2 Sarah Leigh reviewed gene: U2AF2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v6.10 U2AF2 Achchuthan Shanmugasundram Source Expert Review Green was added to U2AF2.
Source NHS GMS was added to U2AF2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.275 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.275 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.275 U2AF2 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: U2AF2.
Tag Q3_23_NHS_review tag was added to gene: U2AF2.
Intellectual disability v5.275 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Intellectual disability v5.275 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.275 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from Developmental disorders to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Intellectual disability v5.273 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Intellectual disability v5.273 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Intellectual disability v5.273 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 33057194
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram edited their review of gene: U2AF2: Changed publications to: 28135719, 31785789, 33057194, 34112922, 36747105, 37092751, 37134193
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Classified gene: U2AF2 as Amber List (moderate evidence)
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Celia Duff, there is sufficient evidence (>3 unrelated cases) available for the association of this gene with global developmental delay, intellectual disability and epilepsy. Hence, this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Classified gene: U2AF2 as Amber List (moderate evidence)
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Celia Duff, there is sufficient evidence (>3 unrelated cases) available for the association of this gene with global developmental delay, intellectual disability and epilepsy. Hence, this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Classified gene: U2AF2 as Amber List (moderate evidence)
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Celia Duff, there is sufficient evidence (>3 unrelated cases) available for the association of this gene with global developmental delay, intellectual disability and epilepsy. Hence, this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.271 U2AF2 Achchuthan Shanmugasundram reviewed gene: U2AF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 31785789, 34112922, 36747105, 37092751, 37134193; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.268 U2AF2 Celia Duff-Farrier changed review comment from: Literature evidence Ref1-5, identification of affected patients in the diagnostic setting (CVA database, 19:55661148:C>T ) and further accounts in open access databases (ClinVar and LOVD), make this gene suitable for clinical review and upgrading to a green gene status on relevant panels. It is associated with a phenotype encompassing dysmorphism, epilepsy, developmental delay, intellectual disability, and brain malformation Ref1-5. There is a recent publication that proposes an extension of this phenotype to include hypomyelination leukodystrophy Ref6. A loss of function mechanism has been suggested, associated with disruption of RNA recognition motifs required for the function of U2AF2 as a pre-mRNA splicing factor Ref4. At least one recurrent pathogenic variant has been identified by this review U2AF2 c.445C>T p.(Arg149Trp). U2AF2 is constrained for missense in gnomAD Z=4.71.
total variants reported
1) De novo U2AF2 (NM_007279.3:c.445C>T p.(Arg149Trp)) recurrent variant; 1x patient in Hiraide (PubMed: 34112922), 1x patient in Kittock (PubMed: 37092751), 2x patients in Kaplanis (Pubmed: 33057194), 7x patients in the Leiden Open Variation Database (LOVD, https://www.lovd.nl/), 1x patient in house BGL and 4x additional on CVA
2) De novo U2AF2 c.603G>T; 1 patient in Wang 2023 (PubMed: 36747105)
3) De novo U2AF2 c.470C>T p.Pro157Leu) in Kuroda (PubMed: 37134193)
4) 9x additional pathogenic or likely pathogenic variants on LOVD
5) 2x additional likely pathogenic variants on ClinVar

References
1.       PubMed: 28135719 McRae (2017)-DDD data
2.       PubMed: 31785789 Turner (2019)-DDD data
3.       PubMed: 34112922 Hiraide (2021) de novo U2AF2 c.445C>T p.R149W
4.       PubMed: 36747105 Wang (2023) de novo U2AF2 c.603G>T, p.163_201del
5.       PubMed: 37092751 Kittock (2023) de novo U2AF2 c.445C>T p.R149W
Possible emerging phenotype of hypomyelinating leukodystrophy
6.       PubMed: 37134193 Kuroda (2023); to: Literature evidence Ref1-5, identification of affected patients in the diagnostic setting (CVA database, 19:55661148:C>T ) and further accounts in open access databases (ClinVar and LOVD), make this gene suitable for clinical review and upgrading to a green gene status on relevant panels. It is associated with a phenotype encompassing dysmorphism, epilepsy, developmental delay, intellectual disability, and brain malformation Ref1-5. There is a recent publication that proposes an extension of this phenotype to include hypomyelination leukodystrophy Ref6. A loss of function mechanism has been suggested, associated with disruption of RNA recognition motifs required for the function of U2AF2 as a pre-mRNA splicing factor Ref4. At least one recurrent pathogenic variant has been identified by this review U2AF2 c.445C>T p.(Arg149Trp). U2AF2 is constrained for missense in gnomAD Z=4.71.
total variants/patients identified
1) De novo U2AF2 (NM_007279.3:c.445C>T p.(Arg149Trp)) recurrent variant; 1x patient in Hiraide (PubMed: 34112922), 1x patient in Kittock (PubMed: 37092751), 2x patients in Kaplanis (Pubmed: 33057194), 7x patients in the Leiden Open Variation Database (LOVD, https://www.lovd.nl/), 1x patient in house BGL and 4x additional on CVA
2) De novo U2AF2 c.603G>T; 1 patient in Wang 2023 (PubMed: 36747105)
3) De novo U2AF2 c.470C>T p.Pro157Leu) in Kuroda (PubMed: 37134193)
4) 9x additional pathogenic or likely pathogenic variants on LOVD
5) 2x additional likely pathogenic variants on ClinVar
6) We are collaborating with a researcher in the USA with a cohort of 40+ cases.


References
1.       PubMed: 28135719 McRae (2017)-DDD data
2.       PubMed: 31785789 Turner (2019)-DDD data
3.       PubMed: 34112922 Hiraide (2021) de novo U2AF2 c.445C>T p.R149W
4.       PubMed: 36747105 Wang (2023) de novo U2AF2 c.603G>T, p.163_201del
5.       PubMed: 37092751 Kittock (2023) de novo U2AF2 c.445C>T p.R149W
Possible emerging phenotype of hypomyelinating leukodystrophy
6.       PubMed: 37134193 Kuroda (2023)
Intellectual disability v5.268 U2AF2 Celia Duff-Farrier reviewed gene: U2AF2: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 28135719):(PMID: 31785789):(PMID: 34112922):(PMID: 36747105):(PMID: 37092751):(PMID 37134193); Phenotypes: intellectual disability, global developmental delay, dysmorphism, epilepsy, brain malformation, microcephaly, possible emerging phenotype of hypomyelinating leukodystrophy.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.597 U2AF2 Ivone Leong Classified gene: U2AF2 as Amber List (moderate evidence)
Intellectual disability v3.597 U2AF2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.597 U2AF2 Ivone Leong Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.510 U2AF2 Zornitza Stark gene: U2AF2 was added
gene: U2AF2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: U2AF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: U2AF2 were set to 33057194
Phenotypes for gene: U2AF2 were set to Developmental disorders
Review for gene: U2AF2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 8 missense, 1 synoymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature