Variant 16-2498261-AT-A details in Genebe, Genetics Data Aggregator

Genes affected

TBC1D24 (HGNC:29203): (TBC1 domain family member 24) 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]

TBC1D24 links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 16-2498261-AT-A is Pathogenic according to our data. Variant chr16-2498261-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 91398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2498261-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D24	NM_001199107.2 linkuse as main transcript	c.1008del	p.His336GlnfsTer12	frameshift_variant	4/8	ENST00000646147.1	NP_001186036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1 linkuse as main transcript	c.1008del	p.His336GlnfsTer12	frameshift_variant	4/8		NM_001199107.2	ENSP00000494678	A1	Q9ULP9-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000739

AC:

AN:

243538

Hom.:

AF XY:

0.0000832

AC XY:

AN XY:

132252

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000154

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000692

AC:

101

AN:

1458980

Hom.:

Cov.:

AF XY:

0.0000662

AC XY:

AN XY:

725406

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000882

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000680

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

DOORS syndrome

Pathogenic:4Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2014	- -
Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Jan 01, 2014	We identified 26 families with DOORS syndrome; each patient had at least 3 of the 5 well-described features of DOORS syndrome, which include deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. A combination of whole-exome sequencing and Sanger sequencing identified homozygous or compound heterozygous pathogenic variants in TBC1D24 in 11 individuals from 9 families. -
Pathogenic, no assertion criteria provided	literature only	Division of Medical Genetics; Sainte-Justine Hospital	Dec 22, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 07, 2019	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2022	Reported in two unrelated individuals with DOORS syndrome, one of whom harbored a different TBC1D24 variant on the opposite allele (Campeau et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28663785, 29655203, 24291220, 27652284, 25169651, 29100083, 25557349, 31589614, 33619735, 34474328) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 29, 2020	PVS1, PS4_moderate, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -

TBC1D24-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2024	Variant summary: TBC1D24 c.1008delT (p.His336GlnfsX12) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 7.4e-05 in 243538 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TBC1D24 causing TBC1D24-Related Disorders, allowing no conclusion about variant significance. c.1008delT has been reported in the literature in individuals affected with Early-onset epileptic encephalopathy with hearing loss (Strazisar_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25557349). ClinVar contains an entry for this variant (Variation ID: 91398). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 16, 2024	The TBC1D24 c.1008delT variant is predicted to result in a frameshift and premature protein termination (p.His336Glnfs*12). This variant has been reported in the compound heterozygous state in individuals with deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures (DOORS) syndrome or with early-onset epileptic encephalopathy (Campeau et al. 2014. PubMed ID: 24291220; Stražišar et al. 2014. PubMed ID: 25557349; Table S7, Hamdan et al. 2017. PubMed ID: 29100083; Table S1, Brunet et al. 2021. PubMed ID: 33619735). To our knowledge, this variant has not been reported to cause autosomal dominant disease, and it was documented in the heterozygous state in at least one unaffected individual (Quaio et al. 2022. PubMed ID: 36147510 ). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in TBC1D24 are expected to be pathogenic for autosomal recessive disease. This variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2018

The c.1008delT pathogenic mutation, located in coding exon 3 of the TBC1D24 gene, results from a deletion of one nucleotide at nucleotide position 1008, causing a translational frameshift with a predicted alternate stop codon (p.H336Qfs*12). In one study, this mutation was detected in two unrelated individuals with features of DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures) syndrome. Only one of these individuals carried a different TBC1D24 alteration on their second allele (Campeau PM et al. Lancet Neurol, 2014 Jan;13:44-58). In a different study, this alteration was reported in siblings with features of DOORS syndrome who both carried a second TBC1D24 alteration on their other allele (Strai&scaron;ar BG et al. Eur. J. Paediatr. Neurol., 2015 Mar;19:251-6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Developmental and epileptic encephalopathy, 16

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 17, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive deafness 86 (MIM#614617), DOORS syndrome (MIM#220500), epilepsy, rolandic, with proxysmal exercise-induce dystonia and writer's cramp (MIM#608105), developmental and epileptic encephalopathy 16 (MIM#615338) and familial, infantile myoclonic epilepsy (MIM#605021). Dominant negative or gain of function is suggested mechanism of autosomal dominant deafness, 65 (MIM#616044) (PMID: 27281533). (I) 0106 - This gene is associated with autosomal recessive disease. Autosomal dominant disease is a rare association. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2) for a recessive condition (20 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in individuals with DOORS syndrome or early-onset epileptic encephalopathy (PMID: 35350397, ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;CN236805:Caused by mutation in the TBC1 domain family, member 24

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 28, 2023

This sequence change creates a premature translational stop signal (p.His336Glnfs*12) in the TBC1D24 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBC1D24 are known to be pathogenic (PMID: 23526554, 24291220). This variant is present in population databases (rs398122967, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive DOORS syndrome or with early-onset epileptic encephalopathy (PMID: 24291220, 25557349). ClinVar contains an entry for this variant (Variation ID: 91398). For these reasons, this variant has been classified as Pathogenic. -

Autosomal dominant nonsyndromic hearing loss 65

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 02, 2020

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

16-2498261-AT-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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