ClinVar Miner

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

gnomAD frequency: 0.00005  dbSNP: rs398122967
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Total submissions: 13
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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
Invitae 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.
PreventionGenetics, part of Exact Sciences RCV004549497 SCV004116563 pathogenic TBC1D24-related disorder 2024-01-16 criteria provided, single submitter 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.
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

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