rs398122967

Variant names:

• chr16-2498261-AT-A
• rs398122967
• NM_001199107.2:c.1008delT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001199107.2(TBC1D24):​c.1008delT​(p.His336GlnfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000677 in 1,611,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: TBC1D24 NM_001199107.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: -1.06

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]

ENSG00000260272 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
TBC1D24	NM_001199107.2	c.1008delT	p.His336GlnfsTer12	frameshift_variant	Exon 4 of 8	ENST00000646147.1	NP_001186036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1	c.1008delT	p.His336GlnfsTer12	frameshift_variant	Exon 4 of 8		NM_001199107.2	ENSP00000494678.1
ENSG00000260272	ENST00000564543.1	c.965+1149delT		intron_variant	Intron 1 of 2	2		ENSP00000455547.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152134 Hom.: 0 Cov.: 33

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: 18 AN: 243538 Hom.: 0 AF XY: 0.0000832 AC XY: 11 AN XY: 132252

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.: 0 Cov.: 32 AF XY: 0.0000662 AC XY: 48 AN XY: 725406

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: 8 AN: 152134 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74322

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.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DOORS syndrome Pathogenic:4 Other:1

Jan 01, 2014

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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. -

Jan 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 22, 2014

Division of Medical Genetics; Sainte-Justine Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 07, 2019

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4

Dec 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 29, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4_moderate, PM2 -

Dec 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

TBC1D24-related disorder Pathogenic:2

Jun 05, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 08, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (Straišar 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

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 02, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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

Other links and lift over

dbSNP: rs398122967; hg19: chr16-2548262;