ClinVar Genomic variation as it relates to human health
NM_178014.4(TUBB):c.895A>G (p.Met299Val)
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_178014.4(TUBB):c.895A>G (p.Met299Val)
Variation ID: 127189 Accession: VCV000127189.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.33 6: 30723957 (GRCh38) [ NCBI UCSC ] 6: 30691734 (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 Sep 9, 2016 May 1, 2024 Mar 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_178014.4:c.895A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_821133.1:p.Met299Val missense NM_001293212.2:c.955A>G NP_001280141.1:p.Met319Val missense NM_001293213.2:c.370-81A>G intron variant NM_001293214.2:c.763A>G NP_001280143.1:p.Met255Val missense NM_001293215.2:c.679A>G NP_001280144.1:p.Met227Val missense NM_001293216.2:c.679A>G NP_001280145.1:p.Met227Val missense NM_178014.3:c.895A>G NR_120608.2:n.451A>G non-coding transcript variant NC_000006.12:g.30723957A>G NC_000006.11:g.30691734A>G NG_034142.1:g.8757A>G P07437:p.Met299Val - Protein change
- M299V, M227V, M255V, M319V
- Other names
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- Canonical SPDI
- NC_000006.12:30723956:A:G
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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
Help
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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TUBB | - | - |
GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37 |
90 | 97 |
Conditions - Germline
Condition
Help
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
Help
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 (4) |
criteria provided, multiple submitters, no conflicts
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Mar 4, 2024 | RCV000115018.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 7, 2023 | RCV003319319.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 22, 2023 | RCV003162533.4 |
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
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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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Pathogenic
(Aug 07, 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: SCV004023429.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
Comment:
Published functional studies demonstrate impaired neuronal morphology, migration, microtubule assembly, and positioning (Breuss et al., 2012; Ngo et al., 2014); Not observed in large population … (more)
Published functional studies demonstrate impaired neuronal morphology, migration, microtubule assembly, and positioning (Breuss et al., 2012; Ngo et al., 2014); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28347630, 23246003, 24833723, 32085672, 30738969, 28412269) (less)
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Pathogenic
(Feb 22, 2023)
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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: SCV003881432.2
First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024 |
Comment:
The c.895A>G (p.M299V) alteration is located in exon 4 (coding exon 4) of the TUBB gene. This alteration results from an A to G substitution … (more)
The c.895A>G (p.M299V) alteration is located in exon 4 (coding exon 4) of the TUBB gene. This alteration results from an A to G substitution at nucleotide position 895, causing the methionine (M) at amino acid position 299 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been previously reported as a de novo occurrence in an individual with microcephaly, brain anomalies, developmental delay, ataxia, retinal dysplasia, and micro-ophthalmia (Breuss, 2012; Ngo, 2014). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (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 6
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV002043789.1
First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021 |
Sex: female
Tissue: Blood
Secondary finding: no
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Pathogenic
(Nov 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Complex cortical dysplasia with other brain malformations 6
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579579.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PM1, PM6, PM2_SUP, PP2, PP3
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Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Mar 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Complex cortical dysplasia with other brain malformations 6
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004812081.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Criteria applied: PS2,PS4_MOD,PS3_SUP,PM2_SUP,PP2,PP3
Clinical Features:
Visual impairment (present) , Intellectual disability (present) , Gait ataxia (present) , Bilateral tonic-clonic seizure (present) , Nocturnal seizures (present) , Abnormal brain morphology (present) … (more)
Visual impairment (present) , Intellectual disability (present) , Gait ataxia (present) , Bilateral tonic-clonic seizure (present) , Nocturnal seizures (present) , Abnormal brain morphology (present) , Generalized non-motor (absence) seizure (present) , Polymicrogyria (present) , Skewfoot (present) , Scoliosis (present) (less)
Sex: male
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Pathogenic
(Dec 27, 2012)
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no assertion criteria provided
Method: literature only
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CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 6
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000148927.3
First in ClinVar: May 05, 2014 Last updated: Sep 23, 2023 |
Comment on evidence:
In a 2-year-old Caucasian boy with complex cortical dysplasia with other brain malformations-6 (CDCBM6; 615771), Breuss et al. (2012) identified a de novo heterozygous mutation … (more)
In a 2-year-old Caucasian boy with complex cortical dysplasia with other brain malformations-6 (CDCBM6; 615771), Breuss et al. (2012) identified a de novo heterozygous mutation in the TUBB gene, resulting in a met299-to-val (M299V) substitution at a highly conserved residue in a loop following helix 9. In vitro functional expression assays showed that the M299V mutation decreased the ability of the protein to assemble into tubulin heterodimers. Overexpression of the mutant protein in the developing mouse brain increased the mitotic index of neurons and decreased the number of neurons in the cortical plate, similar to findings observed in Tubb-null mice. The findings were consistent with a neuronal migratory defect. The patient had severely delayed development, microcephaly (-2.5 SD), and retinal dysplasia. Brain MRI showed focal polymicrogyria, localized band heterotopia, dysmorphic basal ganglia, partial agenesis of the corpus callosum, and hypoplastic and dysplastic cerebellum. (less)
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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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TUBB5 and its disease-associated mutations influence the terminal differentiation and dendritic spine densities of cerebral cortical neurons. | Ngo L | Human molecular genetics | 2014 | PMID: 24833723 |
Mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities. | Breuss M | Cell reports | 2012 | PMID: 23246003 |
Text-mined citations for rs587777355 ...
HelpRecord last updated Jun 23, 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.