Submissions for variant NM_001199107.2(TBC1D24):c.1008del (p.His336fs)

gnomAD frequency: 0.00005  dbSNP: rs398122967

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189708	SCV000243355	pathogenic	not provided	2022-12-28	criteria provided, single submitter	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)
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000076916	SCV000266462	pathogenic	DOORS syndrome	2014-01-01	criteria provided, single submitter	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.
Eurofins Ntd Llc (ga)	RCV000189708	SCV000336179	pathogenic	not provided	2015-10-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470479	SCV000549907	pathogenic	Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24	2023-10-28	criteria provided, single submitter	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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000076916	SCV001150278	pathogenic	DOORS syndrome	2019-06-07	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197830	SCV001368610	pathogenic	Autosomal dominant nonsyndromic hearing loss 65	2020-04-02	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Mayo Clinic Laboratories, Mayo Clinic	RCV000189708	SCV001714540	pathogenic	not provided	2020-10-29	criteria provided, single submitter	clinical testing	PVS1, PS4_moderate, PM2
CeGaT Center for Human Genetics Tuebingen	RCV000189708	SCV002063475	pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426639	SCV002731584	pathogenic	Inborn genetic diseases	2018-01-08	criteria provided, single submitter	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004593986	SCV005087025	pathogenic	Developmental and epileptic encephalopathy, 16	2023-07-17	criteria provided, single submitter	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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004549497	SCV005205289	pathogenic	TBC1D24-related disorder	2024-06-05	criteria provided, single submitter	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.
OMIM	RCV000076916	SCV000108713	pathogenic	DOORS syndrome	2014-01-01	no assertion criteria provided	literature only
Division of Medical Genetics; Sainte-Justine Hospital	RCV000076916	SCV000211969	pathogenic	DOORS syndrome	2014-12-22	no assertion criteria provided	literature only
GeneReviews	RCV000076916	SCV002106362	not provided	DOORS syndrome		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004549497	SCV004116563	pathogenic	TBC1D24-related disorder	2024-01-16	no assertion criteria provided	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.