For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg402 amino acid residue in TUBA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20466733, 20603323, 30517687). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TUBA1A function (PMID: 20603323, 30517687). 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 not expected to disrupt TUBA1A protein function. ClinVar contains an entry for this variant (Variation ID: 7071). This missense change has been observed in individual(s) with lissencephaly (PMID: 17218254, 20466733, 22408144, 24510153). 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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 402 of the TUBA1A protein (p.Arg402His).
ClinVar Genomic variation as it relates to human health
NM_006009.4(TUBA1A):c.1205G>A (p.Arg402His)
Germline
Classification
Help
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.
(11)
Help
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
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006009.4(TUBA1A):c.1205G>A (p.Arg402His)
Variation ID: 7071 Accession: VCV000007071.48
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q13.12 12: 49185161 (GRCh38) [ NCBI UCSC ] 12: 49578944 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 4, 2013 Oct 20, 2024 Jan 16, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006009.4:c.1205G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006000.2:p.Arg402His missense NM_001270399.2:c.1205G>A NP_001257328.1:p.Arg402His missense NM_001270400.2:c.1100G>A NP_001257329.1:p.Arg367His missense NC_000012.12:g.49185161C>T NC_000012.11:g.49578944C>T NG_008966.1:g.8918G>A Q71U36:p.Arg402His - Protein change
- R402H, R367H
- Other names
- -
- Canonical SPDI
- NC_000012.12:49185160:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
dominant_negative_variant; Sequence Ontology [ SO:0002052]
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| TUBA1A | No evidence available | No evidence available |
GRCh38 GRCh37 |
- | - | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
Jun 21, 2013 | RCV000007487.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 1, 2018 | RCV000767403.4 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 16, 2024 | RCV001091238.33 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 1, 2021 | RCV001801361.3 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001291299.3 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 21, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Lissencephaly 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000195270.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
|
|
|
Pathogenic
(Jul 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002228942.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg402 amino acid residue in TUBA1A. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg402 amino acid residue in TUBA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20466733, 20603323, 30517687). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TUBA1A function (PMID: 20603323, 30517687). 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 not expected to disrupt TUBA1A protein function. ClinVar contains an entry for this variant (Variation ID: 7071). This missense change has been observed in individual(s) with lissencephaly (PMID: 17218254, 20466733, 22408144, 24510153). 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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 402 of the TUBA1A protein (p.Arg402His). (less)
|
|
|
Pathogenic
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001814068.2
First in ClinVar: Sep 08, 2021 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate a damaging effect (PMID: 30517687); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in … (more)
Published functional studies demonstrate a damaging effect (PMID: 30517687); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency 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: 24860126, 22264709, 20466733, 20603323, 17218254, 18954413, 29671837, 30744660, 28171541, 22408144, 24510153, 32333414, 24077912, 34958143, 35017693, 30517687, 27535533) (less)
|
|
|
Pathogenic
(Jul 01, 2018)
|
criteria provided, single submitter
Method: literature only
|
Tubulinopathies
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV000898018.1
First in ClinVar: Apr 21, 2019 Last updated: Apr 21, 2019 |
Comment:
A variant that is classified as pathogenic has been identified in the TUBA1A gene in a 2 years old born individual of male sex. The … (more)
A variant that is classified as pathogenic has been identified in the TUBA1A gene in a 2 years old born individual of male sex. The c.1205G>A, p.(Arg402His) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Keays et al. Cell, 2007 PMID: 17218254. HPO-standardized clinical features were: Partial agenesis of the corpus callosum (HP:0001338); Agyria (HP:0031882); Cerebellar vermis hypoplasia (HP:0001320); Hypoplasia of the brainstem (HP:0002365); Cerebellar hypoplasia (HP:0001321); Hypoplastic hippocampus (HP:0025517); Dilation of lateral ventricles (HP:0006956); Gray matter heterotopia (HP:0002281); Congenital microcephaly (HP:0011451); Microcephaly (HP:0000252); Spasticity (HP:0001257); Generalized tonic-clonic seizures (HP:0002069) (less)
Number of individuals with the variant: 11
Age: 0-9 years
Sex: male
|
|
|
Pathogenic
(Nov 01, 2021)
|
criteria provided, single submitter
Method: research
|
Tubulinopathy-associated dysgyria
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg
Accession: SCV002047685.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Clinical Features:
Therapeutic abortion (present) , Simplified gyral pattern (present) , Cerebellar vermis hypoplasia (present) , Hypoplasia of the corpus callosum (present) , Hypoplasia of the corpus … (more)
Therapeutic abortion (present) , Simplified gyral pattern (present) , Cerebellar vermis hypoplasia (present) , Hypoplasia of the corpus callosum (present) , Hypoplasia of the corpus callosum (present) (less)
Segregation observed: no
Secondary finding: no
|
|
|
Pathogenic
(Nov 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247148.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Sep 15, 2010)
|
no assertion criteria provided
Method: literature only
|
LISSENCEPHALY 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027687.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2019 |
Comment on evidence:
In a patient with lissencephaly (LIS3; 611603), Keays et al. (2007) and Poirier et al. (2007) identified a heterozygous de novo 1205G-A transition in exon … (more)
In a patient with lissencephaly (LIS3; 611603), Keays et al. (2007) and Poirier et al. (2007) identified a heterozygous de novo 1205G-A transition in exon 4 of the TUBA1A gene, resulting in an arg402-to-his (R402H) substitution at the beginning of the H11-H12 loop near the interface with beta-tubulin (191130). The patient had microcephaly, agyria, thin corpus callosum, abnormal hippocampus, and hypoplasia of the cerebellar vermis and brainstem, and severe ventricular dilatation. Clinical features included profound mental retardation, spastic tetraplegia, and intractable tonic-clonic seizures. By extensive in vitro functional expression assays, Tian et al. (2010) found that mutant R402H performed like wildtype, although there was a slight reduction in the amount of protein translated and a slight reduction in the formation of tubulin assembly intermediates. There were no obvious effects on de novo heterodimer assembly or microtubule dynamics, suggesting that the disease phenotype is likely to be caused by an effect on other microtubule-dependent processes such as the binding of associated proteins. (less)
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
lissencephaly
Affected status: yes
Allele origin:
unknown
|
University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001479771.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001954967.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963667.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Lissencephaly type 3
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000266413.2
First in ClinVar: Mar 29, 2016 Last updated: Oct 01, 2022 |
Comment:
Classic lissencephaly
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Published functional studies demonstrate a damaging effect (PMID: 30517687); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency 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: 24860126, 22264709, 20466733, 20603323, 17218254, 18954413, 29671837, 30744660, 28171541, 22408144, 24510153, 32333414, 24077912, 34958143, 35017693, 30517687, 27535533)
Comment:
A variant that is classified as pathogenic has been identified in the TUBA1A gene in a 2 years old born individual of male sex. The c.1205G>A, p.(Arg402His) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Keays et al. Cell, 2007 PMID: 17218254. HPO-standardized clinical features were: Partial agenesis of the corpus callosum (HP:0001338); Agyria (HP:0031882); Cerebellar vermis hypoplasia (HP:0001320); Hypoplasia of the brainstem (HP:0002365); Cerebellar hypoplasia (HP:0001321); Hypoplastic hippocampus (HP:0025517); Dilation of lateral ventricles (HP:0006956); Gray matter heterotopia (HP:0002281); Congenital microcephaly (HP:0011451); Microcephaly (HP:0000252); Spasticity (HP:0001257); Generalized tonic-clonic seizures (HP:0002069)
Comment:
Classic lissencephaly
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
dominant_negative_variant
|
|
|
Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg
Accession: SCV002047685.1
|
|
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg402 amino acid residue in TUBA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20466733, 20603323, 30517687). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TUBA1A function (PMID: 20603323, 30517687). 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 not expected to disrupt TUBA1A protein function. ClinVar contains an entry for this variant (Variation ID: 7071). This missense change has been observed in individual(s) with lissencephaly (PMID: 17218254, 20466733, 22408144, 24510153). 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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 402 of the TUBA1A protein (p.Arg402His).
Comment:
Published functional studies demonstrate a damaging effect (PMID: 30517687); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency 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: 24860126, 22264709, 20466733, 20603323, 17218254, 18954413, 29671837, 30744660, 28171541, 22408144, 24510153, 32333414, 24077912, 34958143, 35017693, 30517687, 27535533)
Comment:
A variant that is classified as pathogenic has been identified in the TUBA1A gene in a 2 years old born individual of male sex. The c.1205G>A, p.(Arg402His) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Keays et al. Cell, 2007 PMID: 17218254. HPO-standardized clinical features were: Partial agenesis of the corpus callosum (HP:0001338); Agyria (HP:0031882); Cerebellar vermis hypoplasia (HP:0001320); Hypoplasia of the brainstem (HP:0002365); Cerebellar hypoplasia (HP:0001321); Hypoplastic hippocampus (HP:0025517); Dilation of lateral ventricles (HP:0006956); Gray matter heterotopia (HP:0002281); Congenital microcephaly (HP:0011451); Microcephaly (HP:0000252); Spasticity (HP:0001257); Generalized tonic-clonic seizures (HP:0002069)
Comment:
Classic lissencephaly
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Tubulinopathies Overview. | Adam MP | - | 2021 | PMID: 27010057 |
| The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy. | Hebebrand M | Orphanet journal of rare diseases | 2019 | PMID: 30744660 |
| TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity. | Aiken J | Human molecular genetics | 2019 | PMID: 30517687 |
| Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly. | Di Donato N | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29671837 |
| The wide spectrum of tubulinopathies: what are the key features for the diagnosis? | Bahi-Buisson N | Brain : a journal of neurology | 2014 | PMID: 24860126 |
| DTI tractography of lissencephaly caused by TUBA1A mutation. | Kamiya K | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2014 | PMID: 24510153 |
| Lissencephaly and band heterotopia: LIS1, TUBA1A, and DCX mutations in Hungary. | Mokánszki A | Journal of child neurology | 2012 | PMID: 22408144 |
| Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway. | Tian G | Human molecular genetics | 2010 | PMID: 20603323 |
| TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins. | Kumar RA | Human molecular genetics | 2010 | PMID: 20466733 |
| Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations. | Bahi-Buisson N | Journal of medical genetics | 2008 | PMID: 18728072 |
| Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A). | Poirier K | Human mutation | 2007 | PMID: 17584854 |
| Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. | Keays DA | Cell | 2007 | PMID: 17218254 |
| click to load more click to collapse | ||||
Text-mined citations for rs137853044 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.