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Intellectual disability v8.97 TBC1D7 Sarah Leigh Tag Q3_24_promote_green was removed from gene: TBC1D7.
Tag Q3_24_NHS_review was removed from gene: TBC1D7.
Intellectual disability v8.97 TBC1D7 Sarah Leigh reviewed gene: TBC1D7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 TBC1D7 Sarah Leigh Source NHS GMS was added to TBC1D7.
Source Expert Review Green was added to TBC1D7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.52 TBC1D7 Achchuthan Shanmugasundram Tag watchlist was removed from gene: TBC1D7.
Tag Q3_24_promote_green tag was added to gene: TBC1D7.
Tag Q3_24_NHS_review tag was added to gene: TBC1D7.
Intellectual disability v6.52 TBC1D7 Achchuthan Shanmugasundram Classified gene: TBC1D7 as Amber List (moderate evidence)
Intellectual disability v6.52 TBC1D7 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Frances Elmslie, PMID:36669495 reported an additional case with compound heterozygous variants (identified via trio RNA-Seq) and presenting with a neurodevelopmental disorder involving mild intellectual disability.

Hence, this gene can be promoted to green rating with the current evidence (three unrelated cases and functional studies) in the next GMS update.
Intellectual disability v6.52 TBC1D7 Achchuthan Shanmugasundram Gene: tbc1d7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.51 TBC1D7 Achchuthan Shanmugasundram Publications for gene: TBC1D7 were set to PMID: 23687350; 24515783
Intellectual disability v6.50 TBC1D7 Achchuthan Shanmugasundram reviewed gene: TBC1D7: Rating: GREEN; Mode of pathogenicity: None; Publications: 36669495; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v6.50 TBC1D7 Frances Elmslie reviewed gene: TBC1D7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24515783, 23687350, 36669495, 35584673; Phenotypes: Macrocephaly, intellectual disability, megalencephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v4.27 TBC1D7 Arina Puzriakova Phenotypes for gene: TBC1D7 were changed from intellectual disability; macrocephaly; megalencephaly to Macrocephaly/megalencephaly syndrome, autosomal recessive, OMIM:248000
Intellectual disability v3.170 TBC1D2B Konstantinos Varvagiannis gene: TBC1D2B was added
gene: TBC1D2B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TBC1D2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D2B were set to 32623794
Phenotypes for gene: TBC1D2B were set to Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Penetrance for gene: TBC1D2B were set to Complete
Review for gene: TBC1D2B was set to AMBER
Added comment: Harms et al (2020 - PMID: 32623794) report on 3 unrelated individuals with biallelic pLoF TBC1D2B variants.

Features included cognitive impairment (mild ID in one case, regression at the age of 12y in another, hypotonia and delayed milestones in a third aged 8m), seizures (3/3 - variable age of onset) and/or gingival overgrowth (2/3 - prior to initiation of AEDs). Other findings included behavioral abnormalities, mandibular anomalies, abnormal brain imaging and ophthalmologic or (rarely) audiometric evaluations.

All were born to non-consanguineous couples and additional investigations were performed in some.

Variants were identified by WES or trio WGS, with Sanger confirmation/compatible segregation analyses.

In line with the pLoF variants, mRNA studies in fibroblasts from 2 unrelated affected individuals demonstrated significantly reduced (~80-90%) TBC1C2D mRNA levels compared to controls, restored following cycloheximide treatment. Protein was absent in patient fibroblasts.

TBC-domain containing GTPase activating proteins are known as key regulators of RAB GTPase activity. TBC1D2B was shown to colocalize with RAB5-positive endocytic vesicles. CRISPR/Cas9-mediated ko of TBC1D2B in HeLa cells suggested a role in EGF receptor endocytosis and decreased cell viability of TBC1D2B-deficient HeLa cells upon serum deprivation.

Genes encoding other TBC domain-containg GTPase-activating proteins, e.g. TBC1D7 and TBC1D20, TBC1D24 are associated with recessive neurodevelopmental disorders (with ID and/or seizures) and the pathophysiological defect in TBC1D2B-related disorder (deficit in vesicle trafficking and/or cell survival) is proposed to be similar to that of TBC1D24.

Overall this gene can be considered for inclusion with amber/green rating in the ID panel and green in epilepsy panel.
Sources: Literature
Intellectual disability v2.774 TBC1D7 Rebecca Foulger commented on gene: TBC1D7: Added watchlist tag.
Intellectual disability v2.774 TBC1D7 Rebecca Foulger Tag watchlist tag was added to gene: TBC1D7.
Intellectual disability v2.774 TBC1D7 Rebecca Foulger Classified gene: TBC1D7 as Amber List (moderate evidence)
Intellectual disability v2.774 TBC1D7 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber. Gene added to panel and reviewed Amber by Konstantinos Varvagiannis. Currently only 2 unrelated ID cases from 2 publications (PMID:23687350 Capo-Chichi et al 2013 and PMID:24515783 Alfaiz et al 2014). TBC1D7 is not currently associated with a phenotype in DD-Gene2Phenotype. Therefore rated Amber awaiting further cases.
Intellectual disability v2.774 TBC1D7 Rebecca Foulger Gene: tbc1d7 has been classified as Amber List (Moderate Evidence).
Intellectual disability TBC1D7 Konstantinos Varvagiannis reviewed gene: TBC1D7
Intellectual disability TBC1D7 Konstantinos Varvagiannis edited their review of gene: TBC1D7
Intellectual disability TBC1D7 Konstantinos Varvagiannis Added gene to panel