ClinVar Genomic variation as it relates to human health
NM_001199107.2(TBC1D24):c.457G>A (p.Glu153Lys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(3); Likely pathogenic(5); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001199107.2(TBC1D24):c.457G>A (p.Glu153Lys)
Variation ID: 207499 Accession: VCV000207499.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2496605 (GRCh38) [ NCBI UCSC ] 16: 2546606 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 7, 2017 May 1, 2024 Jul 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001199107.2:c.457G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001186036.1:p.Glu153Lys missense NM_020705.3:c.457G>A NP_065756.1:p.Glu153Lys missense NC_000016.10:g.2496605G>A NC_000016.9:g.2546606G>A NG_028170.1:g.26460G>A - Protein change
- E153K
- Other names
- p.E153K:GAG>AAG
- Canonical SPDI
- NC_000016.10:2496604:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Exome Aggregation Consortium (ExAC) 0.00008
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TBC1D24 | - | - |
GRCh38 GRCh37 |
923 | 977 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 18, 2023 | RCV000189685.20 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 12, 2018 | RCV000850506.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 9, 2023 | RCV000558935.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 13, 2017 | RCV000614904.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 7, 2019 | RCV000995887.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 16, 2016 | RCV002311285.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 15, 2022 | RCV002468572.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Nov 13, 2017)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711638.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Glu153Lys variant in TBC1D24 has been indentified in 5 individuals with TB C1D24-associated features. One individual had nonsyndromic hearing loss and was compound heterozygote … (more)
The p.Glu153Lys variant in TBC1D24 has been indentified in 5 individuals with TB C1D24-associated features. One individual had nonsyndromic hearing loss and was compound heterozygote for this variant as well as a VUS variant, both of which s egregated in a sibling with hearing loss (Bakhchane 2015). This variant has now been identified by our laboratory in an individual with hearing loss in trans wi th a TBC1D24 variant of uncertain significance (LMM data). Another individual p resented with a seizure disorder who initially passed an early hearing screen bu t developed profound deafness reported by 5 years of age (Ngoh 2017). This indiv idual was compound heterozygous for the p.Glu153Lys variant and a pathogenic var iant in TBC1D24, and both variants segregated in a sibling with similar seizure manifestations but was not reported to have hearing loss at 3 years of age (Ngoh 2017). In addition, the variant was reported in one homozygote individual and h is sibling (Poulat 2015), and one compound heterozygote individual (Ragona 2017) , all presenting with TBC1D24-related seizures, but hearing loss was not reporte d. The p.Glu153Lys variant has been identified in 3/20274 Finnish and 12/110864 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs376712059), and has been reported in ClinVar (Variati on ID 207499). Although there is a wide range of clinical features reported for affected individuals that carry this variant, these features are consistent with the phenotypic spectrum associated with TBC1D24-associated disorders. In additi on, the segregation of the variant in similarly affected family members in three unrelated families supports a causative role for the variant. Furthermore, comp utational prediction tools and conservation analysis suggest that the p.Glu153Ly s variant may impact the protein. In summary, although additional studies are r equired to fully establish its clinical significance, this variant is likely pat hogenic. ACMG/AMP Criteria applied: PP1_S, PM3_S, PM2, PM3, PP3, PP4. (less)
Number of individuals with the variant: 2
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Likely pathogenic
(Oct 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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DOORS syndrome
Autosomal recessive nonsyndromic hearing loss 86 Autosomal dominant nonsyndromic hearing loss 65 Developmental and epileptic encephalopathy, 16 Familial infantile myoclonic epilepsy
Affected status: yes
Allele origin:
germline
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Baylor Genetics
Accession: SCV000992709.1
First in ClinVar: Sep 21, 2019 Last updated: Sep 21, 2019 |
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Pathogenic
(Jun 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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DOORS syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150277.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: male
Tissue: blood
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Likely pathogenic
(Jul 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000243331.18
First in ClinVar: Aug 07, 2015 Last updated: Jul 29, 2023 |
Comment:
Identified with a second TBC1D24 variant on the opposite allele (in trans) in siblings with nonsyndromic hearing loss in published literature (Bakhchane et al., 2015); … (more)
Identified with a second TBC1D24 variant on the opposite allele (in trans) in siblings with nonsyndromic hearing loss in published literature (Bakhchane et al., 2015); authors propose that the second variant may be hypomorphic, resulting in a milder phenotype; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24291220, 27259978, 25769375, 28428906, 32004315, 28292732, 27652284, 27281533, 31216405, 33619735, 34852372, Timpanaro2021[Review], 28726039, 33986365, 35350397, 26371875) (less)
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Pathogenic
(Jun 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Caused by mutation in the TBC1 domain family, member 24
Developmental and epileptic encephalopathy, 1 Autosomal dominant nonsyndromic hearing loss 65
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000654208.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TBC1D24 protein function. ClinVar contains an entry for this variant (Variation ID: 207499). This missense change has been observed in individuals with autosomal recessive TBC1D24-related conditions (PMID: 25769375, 26371875, 28428906). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs376712059, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 153 of the TBC1D24 protein (p.Glu153Lys). (less)
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Uncertain significance
(Apr 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000846204.4
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The p.E153K variant (also known as c.457G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide … (more)
The p.E153K variant (also known as c.457G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 457. The glutamic acid at codon 153 is replaced by lysine, an amino acid with similar properties. This alteration was detected in the homozygous state in two brothers of Algerian descent from a consanguineous family with early onset focal myoclonic fits that evolved to generalized myoclonus, developmental delay, moderate learning concerns, and a diagnosis of familial infantile myoclonic epilepsy; however, TBC1D24 was the only gene analyzed (Poulat AL, Epilepsy Res. 2015 Mar; 111:72-7). In addition, this alteration was detected in trans with another alteration in the TBC1D24 via whole exome sequencing in two siblings with nonsyndromic hearing loss (Bakhchane A, PLoS ONE 2015; 10(9):e0138072). This variant was previously reported in the SNPDatabase as rs376712059. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/12876) total alleles studied and 0.01% (1/8536) European American alleles. Based on data from ExAC, the A allele has an overall frequency of approximately <0.01% (8/104258) total alleles studied (TCGA excluded). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this variant remains unclear. (less)
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Likely pathogenic
(Dec 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV004229318.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with epileptic encephalopathy and appears to segregate with disease in at least one family with infantile myoclonic epilepsy. Computational tools predict that this variant is damaging. (less)
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Pathogenic
(Mar 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003819865.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Nov 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 16
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002765051.2
First in ClinVar: Dec 24, 2022 Last updated: Apr 15, 2024 |
Comment:
Criteria applied: PS1,PS4_MOD,PM2_SUP
Clinical Features:
Aggressive behavior (present) , Focal clonic seizure (present) , Bilateral tonic-clonic seizure with focal onset (present) , Myoclonus (present) , Hallucinations (present) , Intellectual disability, … (more)
Aggressive behavior (present) , Focal clonic seizure (present) , Bilateral tonic-clonic seizure with focal onset (present) , Myoclonus (present) , Hallucinations (present) , Intellectual disability, moderate (present) (less)
Sex: male
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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De novo variants in neurodevelopmental disorders-experiences from a tertiary care center. | Brunet T | Clinical genetics | 2021 | PMID: 33619735 |
The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors. | Lin L | PLoS genetics | 2020 | PMID: 32004315 |
TBC1D24 gene mRNA expression in a boy with early infantile epileptic encephalopathy-16. | Salemi M | Acta neurologica Belgica | 2020 | PMID: 28726039 |
Reanalysis of Clinical Exome Sequencing Data. | Liu P | The New England journal of medicine | 2019 | PMID: 31216405 |
TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus. | Ngoh A | Tremor and other hyperkinetic movements (New York, N.Y.) | 2017 | PMID: 28428906 |
Alternating Hemiplegia and Epilepsia Partialis Continua: A new phenotype for a novel compound TBC1D24 mutation. | Ragona F | Seizure | 2017 | PMID: 28292732 |
TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features. | Balestrini S | Neurology | 2016 | PMID: 27281533 |
Recessive TBC1D24 Mutations Are Frequent in Moroccan Non-Syndromic Hearing Loss Pedigrees. | Bakhchane A | PloS one | 2015 | PMID: 26371875 |
Homozygous TBC1D24 mutation in two siblings with familial infantile myoclonic epilepsy (FIME) and moderate intellectual disability. | Poulat AL | Epilepsy research | 2015 | PMID: 25769375 |
Text-mined citations for rs376712059 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.