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| Intellectual disability v10.41 | TMEM63B | Achchuthan Shanmugasundram Phenotypes for gene: TMEM63B were changed from Developmental and epileptic encephalopathy 118, OMIM:621250; developmental and epileptic encephalopathy, MONDO:0100062; autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,; lung disorder, MONDO:0005275 to Developmental and epileptic encephalopathy 118, OMIM:621250; developmental and epileptic encephalopathy, MONDO:0100062; autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder; lung disorder, MONDO:0005275 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.40 | TMEM63B | Eleanor Williams Phenotypes for gene: TMEM63B were changed from Developmental and epileptic encephalopathy 118, OMIM:621250 to Developmental and epileptic encephalopathy 118, OMIM:621250; developmental and epileptic encephalopathy, MONDO:0100062; autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,; lung disorder, MONDO:0005275 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.39 | TMEM63B | Eleanor Williams Publications for gene: TMEM63B were set to 37421948; 42259295 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.38 | TMEM63B | Eleanor Williams Publications for gene: TMEM63B were set to 37421948 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.37 | TMEM63B | Eleanor Williams Added comment: Comment on mode of inheritance: There are sufficient biallelic cases with loss of function variants and phenotype that includes moderate-severe developmental delay as well as lung disease to change the mode of inheritance to BOTH monoallelic and biallelic, autosomal or pseudoautosomal subject to GMS review. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.37 | TMEM63B | Eleanor Williams Mode of inheritance for gene: TMEM63B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.36 | TMEM63B | Eleanor Williams Tag Q2_26_MOI tag was added to gene: TMEM63B. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.36 | TMEM63B |
Eleanor Williams changed review comment from: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046). PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921. The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction. The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD. Moderate to severe developmental delay was reported in all individuals.; to: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921. The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction. The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD. Moderate to severe developmental delay was reported in all individuals. |
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| Intellectual disability v10.36 | TMEM63B | Eleanor Williams Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.36 | TMEM63B |
Eleanor Williams commented on gene: TMEM63B: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046). PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921. The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction. The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD. Moderate to severe developmental delay was reported in all individuals. |
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| Intellectual disability v10.36 | TMEM63B | Eleanor Williams reviewed gene: TMEM63B: Rating: GREEN; Mode of pathogenicity: None; Publications: 42259295; Phenotypes: autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,, lung disorder, MONDO:0005275; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.334 | TMEM63B | Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.334 | TMEM63B | Arina Puzriakova Phenotypes for gene: TMEM63B were changed from developmental and epileptic encephalopathy, MONDO:0100062 to Developmental and epileptic encephalopathy 118, OMIM:621250 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.333 | TMEM63B | Arina Puzriakova Tag gene-checked was removed from gene: TMEM63B. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v6.12 | TMEM63B | Eleanor Williams Tag gene-checked tag was added to gene: TMEM63B. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v6.11 | TMEM63B | Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: TMEM63B. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v6.11 | TMEM63B | Sarah Leigh reviewed gene: TMEM63B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v6.10 | TMEM63B |
Achchuthan Shanmugasundram Source Expert Review Green was added to TMEM63B. Source NHS GMS was added to TMEM63B. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| Intellectual disability v5.221 | TMEM63B | Achchuthan Shanmugasundram Classified gene: TMEM63B as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v5.221 | TMEM63B | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (17 unrelated cases) in support of promoting this gene to green rating in the next GMS review. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v5.221 | TMEM63B | Achchuthan Shanmugasundram Gene: tmem63b has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v5.220 | TMEM63B | Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: TMEM63B. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v5.220 | TMEM63B |
Achchuthan Shanmugasundram gene: TMEM63B was added gene: TMEM63B was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: TMEM63B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TMEM63B were set to 37421948 Phenotypes for gene: TMEM63B were set to developmental and epileptic encephalopathy, MONDO:0100062 Review for gene: TMEM63B was set to GREEN Added comment: PMID:37421948 - 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment. Sources: Literature |
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