ClinVar Genomic variation as it relates to human health
NM_006086.4(TUBB3):c.763G>A (p.Val255Ile)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006086.4(TUBB3):c.763G>A (p.Val255Ile)
Variation ID: 372654 Accession: VCV000372654.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q24.3 16: 89935214 (GRCh38) [ NCBI UCSC ] 16: 90001622 (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 9, 2017 Feb 20, 2024 Sep 9, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006086.4:c.763G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006077.2:p.Val255Ile missense NM_001197181.2:c.547G>A NP_001184110.1:p.Val183Ile missense NC_000016.10:g.89935214G>A NC_000016.9:g.90001622G>A NG_027810.1:g.18206G>A - Protein change
- V183I, V255I
- Other names
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- Canonical SPDI
- NC_000016.10:89935213: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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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TUBB3 | No evidence available | No evidence available |
GRCh38 GRCh37 |
295 | 366 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Sep 9, 2022 | RCV000412886.7 | |
TUBB3-related disorder
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not provided (1) |
no classification provided
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- | RCV001788210.1 |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 8, 2022 | RCV001843359.5 |
Submissions - Germline
Classification
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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
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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
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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
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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
(Oct 12, 2016)
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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: SCV000491036.1
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Comment:
The V255I variant in the TUBB3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The … (more)
The V255I variant in the TUBB3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V255I variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V255I variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The V255I variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Complex cortical dysplasia with other brain malformations 1
Affected status: yes
Allele origin:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV002102522.1
First in ClinVar: Mar 09, 2022 Last updated: Mar 09, 2022 |
Sex: female
Tissue: Blood
Secondary finding: no
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Pathogenic
(Jul 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Complex cortical dysplasia with other brain malformations 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764939.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Motor delay (present) , Abnormal corpus callosum morphology (present) , Cerebral palsy (present) , Hemiplegia (present)
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Pathogenic
(Sep 09, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003305072.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 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) performed at Invitae indicates that this missense variant is expected to disrupt TUBB3 protein function. ClinVar contains an entry for this variant (Variation ID: 372654). This missense change has been observed in individual(s) with clinical features of TUBB3-related conditions (PMID: 34863918). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 255 of the TUBB3 protein (p.Val255Ile). (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808416.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958980.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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TUBB3-Related Disorder
Affected status: yes
Allele origin:
de novo
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GenomeConnect - Brain Gene Registry
Accession: SCV002030752.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 07-18-2019 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided … (more)
Variant interpreted as Pathogenic and reported on 07-18-2019 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR ) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. (less)
Clinical Features:
Overgrowth (present) , Short stature (present) , Abnormality of eye movement (present) , Myopia (present) , Ear malformation (present) , Conductive hearing impairment (present) , … (more)
Overgrowth (present) , Short stature (present) , Abnormality of eye movement (present) , Myopia (present) , Ear malformation (present) , Conductive hearing impairment (present) , Hearing impairment (present) , Abnormality of the nervous system (present) , Cerebral palsy (present) , Cognitive impairment (present) , Abnormality of coordination (present) , EEG abnormality (present) , Hypertonia (present) , Seizure (present) , Anxiety (present) , Short attention span (present) , Abnormality of facial musculature (present) , Abnormal muscle physiology (present) , Abnormal EKG (present) , Feeding difficulties (present) (less)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2019-07-18
Testing laboratory interpretation: Pathogenic
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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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Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant. | de Boer E | European journal of medical genetics | 2022 | PMID: 34863918 |
Text-mined citations for rs1057517908 ...
HelpRecord last updated Oct 08, 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.