TBC1D24

protein-coding

TBC1 domain family member 24, the group of TLDc domain containing

Gene summary

This gene encodes a protein with a conserved domain, referred to as the TBC domain, characteristic of proteins which interact with GTPases. TBC domain proteins may serve as GTPase-activating proteins for a particular group of GTPases, the Rab (Ras-related proteins in brain) small GTPases which are involved in the regulation of membrane trafficking. Mutations in this gene are associated with familial infantile myoclonic epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2011]

Previous symbols:

DFNB86

MANE transcript

NM_001199107.2

Inheritance

AR, AD

ClinVar variants

P:131U:446B:238

Top phenotype

Deafness, onychodystrophy, osteodystrophy, impaired intellectual development, and seizures (DOORS) syndrome; Deafness, autosomal recessive 86

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr16:2,475,051-2,509,671

External References & Databases

Ensembl (ENSG00000162065)

Transcript & Mutation Effects

hg38 • Region Span ~34.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

DOORS syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009079

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 65STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014470

Submitter: Labcorp Genetics (formerly Invitae)

DOORS syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009079

Submitter: ClinGen

Autosomal recessive TBC1D24-related syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness, to benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct phenotypic correlation with pathogenic variant type or location yet, but patterns are emerging (Balestrini 2016). Sensorineural hearing loss is a key feature of DOORS syndrome, which is characterized by deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (Campeau 2014). Isolated seizure disorders without any reported deafness have been seen (Balestrini 2016). In contrast, two of the families reported to have nonsyndromic hearing loss caused by variants in TBC1D24 were shown to have no history of seizures (Rehman 2014). Further, two independent reports identified the same variant in TBC1D24 to be segregating in an autosomal dominant manner with nonsyndromic hearing loss (Azaiez 2014, Zhang 2014). The strength of the evidence that this gene can cause autosomal dominant nonsyndromic hearing loss is Limited, however. Currently there is not enough evidence to treat nonsyndromic hearing loss or isolated seizures as distinct conditions, especially because those affected with DOORS syndrome have both hearing loss and seizure phenotypes. Experimental evidence has implicated a role for the TBC1D24 gene in neuronal development, including neurite length and arborization (Corbett 2010, Falace 2010, Milh 2013) as well as in protection from neuronal oxidative stress (Finelli 2016). While the gene has been shown to be expressed in the murine cochlea (Rehman 2014, Azaiez 2014, Zhang 2014) , there is no further evidence for a potential mechanism of hearing loss. In summary, the TBC1D24 gene is definitively associated with a spectrum of autosomal recessive phenotypes which the Hearing Loss and Epilepsy Gene Curation Expert Panels propose are a spectrum of DOORS syndrome. This classification was approved by both the ClinGen Hearing Loss and Epilepsy Working Groups on 3/19/19 (SOP Version 6).

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

*TBC1D24* was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2014 by two groups (Zhang et al and Azaiez et al., PMIDs: 24729547, 24729539). At least 8 missense variants that have been reported in 12 humans in 6 publications are included in this curation (PMID: 24729547, 24729539, 33281559, 33986365, 36597107, 38413761). Variants in this gene have segregated with disease in 64 additional family members (PMIDs: 24729547, 24729539, 33281559, 33986365, 38413761). This gene-disease relationship is also supported by expression studies (PMIDs: 224729547, 24729539, 32987832). Other than expression in mouse cochlear hair cells, there is no experimental evidence for a dominant disease. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 3/27/2018 as per SOP v6. It was reevaluated on 5/3/2024 using SOP v10. As a result of this reevaluation, the classification did not change. New case-level and functional evidence has been reviewed or added, but the classification did not change (PMIDs: 36597107, 34440452, 32860223, 38413761, 32987832).

malignant migrating partial seizures of infancySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017385

Submitter: Orphanet

familial infantile myoclonic epilepsyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011506

Submitter: G2P

autosomal recessive nonsyndromic hearing loss 86LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013826

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 86STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013826

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 65MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014470

Submitter: Ambry Genetics

familial infantile myoclonic epilepsyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011506

Submitter: Ambry Genetics

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

DOORS syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009079

Submitter: G2P

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

DOORS syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009079

Submitter: Orphanet

progressive myoclonic epilepsy with dystoniaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018126

Submitter: Orphanet

focal epilepsy-intellectual disability-cerebro-cerebellar malformationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018125

Submitter: Orphanet

autosomal dominant nonsyndromic hearing loss 65LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014470

Submitter: PanelApp Australia

DOORS syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009079

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014133

Submitter: PanelApp Australia

DOORS syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009079

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, onychodystrophy, osteodystrophy, impaired intellectual development, and seizures (DOORS) syndrome; Deafness, autosomal recessive 86AD/AR

Manifestation: Audiologic/Otolaryngologic; Dermatologic; Musculoskeletal; Neurologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 10741954; 20797691; 20727515; 21087195; 22211675; 23343562; 23526554; 24291220; 24387994; 24729539; 24729547; 31257402

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBC1D24 variants in ClinVar

37 Conditions Cataloged

not providedTotal: 816

Autosomal dominant nonsyndromic hearing loss 65Total: 740

Developmental and epileptic encephalopathy, 1Total: 732

Inborn genetic diseasesTotal: 166

not specifiedTotal: 136

TBC1D24-related disorderTotal: 91

Familial infantile myoclonic epilepsyTotal: 79

Developmental and epileptic encephalopathy, 16Total: 57

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001199107.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	211 clinvar	4 clinvar	224
missense	14 clinvar	40 clinvar	432 clinvar	22 clinvar	1 clinvar	509
nonsense	20 clinvar	9 clinvar	1 clinvar			30
start loss		1 clinvar	1 clinvar			2
frameshift	26 clinvar	9 clinvar	1 clinvar			36
splice donor/acceptor (+/-2bp)	3 clinvar	9 clinvar	2 clinvar			14
Total	63	68	446	233	5	815

Highest pathogenic variant AF is 0.00006765505

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001199107.2	RefSeq	NP_001186036.1	7	MANE Select
ENST00000646147.1	Ensembl	ENSP00000494678.1	7	MANE Select
NM_020705.3	RefSeq	NP_065756.1	6	Standard
ENST00000562105.2	Ensembl	ENSP00000457896.2	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
TBC/RABGAPs
Membrane Trafficking
Rab regulation of trafficking

Biological Process

neuron projection development
positive regulation of GTPase activity
regulation of cilium assembly

Molecular Function

GTPase activator activity
protein binding

Cellular Component

cytoplasm
plasma membrane
cell junction
cytoplasmic vesicle membrane
neuromuscular junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000293970
Coding exons: 7
Length: 30589
Individuals with no LoFs: 124772
Homozygous LoFs: 0
Heterozygous LoFs: 78
Defined: 124850
p: 0.000312

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.757	312	352	0.886	0.0000257	3622
Missense (PolyPhen)		95	113.76	0.83506		1169
Synonymous	-0.993	179	163	1.10	0.0000136	1098
Loss of Function	1.14	15	20.6	0.730	9.00e-7	244

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00040	0.00039	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.00031	0.00030	rare
East Asian	0.000056	0.000056	rare
Finnish	0.00032	0.00032	rare
European (Non-Finnish)	0.00042	0.00041	rare
South Asian	0.00013	0.00013	rare
Other	0.00083	0.00082	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May act as a GTPase-activating protein for Rab family protein(s). Involved in neuronal projections development, probably through a negative modulation of ARF6 function. {ECO:0000269|PubMed:20727515, ECO:0000269|PubMed:20797691}.;
Disease: DISEASE: Epileptic encephalopathy, early infantile, 16 (EIEE16) [MIM:615338]: A severe autosomal recessive neurologic disorder characterized by onset of seizures in the first weeks or months of life. Seizures can be of various types, are unresponsive to medication, last for long periods of time, and occur frequently. Affected infants show psychomotor regression or lack of psychomotor development, as well as other neurologic features such as extrapyramidal signs and hypotonia. Most die in childhood. {ECO:0000269|PubMed:23526554, ECO:0000269|PubMed:27541164}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant, 65 (DFNA65) [MIM:616044]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA65 is characterized by post- lingual onset of slowly progressive hearing loss in the third decade. Initially affecting the high frequencies, the hearing loss eventually affects all frequencies and results in severe to profound deafness in the seventh decade. Vestibular function is normal. {ECO:0000269|PubMed:24729539, ECO:0000269|PubMed:24729547}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndrome (DOORS) [MIM:220500]: A syndrome characterized by sensorineural deafness, mental retardation, hypoplastic or absent nails, small or absent distal phalanges of hands and feet. Additional features include coarse facies, a large nose with wide nasal bridge, bulbous tip and anteverted nares, a long prominent philtrum and downturned corners of the mouth. Progressive neurological manifestations include seizures from infancy, optic atrophy, and peripheral polyneuropathy. {ECO:0000269|PubMed:24291220}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 86 (DFNB86) [MIM:614617]: A form of non-syndromic deafness characterized by prelingual onset of profound sensorineural hearing loss affecting all frequencies. {ECO:0000269|PubMed:24387994}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.612
RVIS EVS: 0.6
RVIS percentile EVS: 82.83

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.404

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium