ClinVar Genomic variation as it relates to human health
NM_006009.4(TUBA1A):c.791G>A (p.Arg264His)
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(1); Likely pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006009.4(TUBA1A):c.791G>A (p.Arg264His)
Variation ID: 287392 Accession: VCV000287392.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.12 12: 49185575 (GRCh38) [ NCBI UCSC ] 12: 49579358 (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 Feb 13, 2018 Dec 24, 2022 Oct 23, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006009.4:c.791G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006000.2:p.Arg264His missense NM_001270399.2:c.791G>A NP_001257328.1:p.Arg264His missense NM_001270400.2:c.686G>A NP_001257329.1:p.Arg229His missense NC_000012.12:g.49185575C>T NC_000012.11:g.49579358C>T NG_008966.1:g.8504G>A - Protein change
- R264H, R229H
- Other names
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- Canonical SPDI
- NC_000012.12:49185574:C:T
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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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TUBA1A | No evidence available | No evidence available |
GRCh38 GRCh37 |
355 | 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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Oct 19, 2020 | RCV000381002.7 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2020 | RCV000726002.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 1, 2018 | RCV000767451.1 |
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
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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 19, 2017)
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criteria provided, single submitter
Method: clinical testing
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Lissencephaly due to TUBA1A mutation
(Sporadic)
Affected status: yes
Allele origin:
de novo
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Prenatal Medicine Munich, Prenatal Medicine Munich
Accession: SCV000680095.1
First in ClinVar: Feb 13, 2018 Last updated: Feb 13, 2018 |
Sex: male
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Likely pathogenic
(Apr 05, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000341151.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely pathogenic
(Jul 01, 2018)
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criteria provided, single submitter
Method: literature only
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Tubulinopathies
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV000898066.1
First in ClinVar: Apr 21, 2019 Last updated: Apr 21, 2019 |
Comment:
A variant that is classified as likely pathogenic has been identified in the TUBA1A gene in a born individual of unknown sex. The c.791G>A, p.(Arg264His) … (more)
A variant that is classified as likely pathogenic has been identified in the TUBA1A gene in a born individual of unknown sex. The c.791G>A, p.(Arg264His) variant has been reported as a variant of germline/unknown origin. This variant and associated phenotype was previously reported by Alby et al. Birth Defects Res A Clin Mol Teratol, 2016 (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446965.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Micrognathia (present) , Corpus callosum, agenesis of (present) , Lissencephaly (present) , Abnormal brainstem morphology (present) , Widened cerebral subarachnoid space (present)
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Uncertain significance
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Lissencephaly due to TUBA1A mutation
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV000807275.2
First in ClinVar: Feb 13, 2018 Last updated: Dec 11, 2022 |
Comment:
This variant was found once in our laboratory de novo in a newborn female with IUGR, hypotonia, seizures, microcephaly, lissencephaly, cerebellar hypoplasia, tachycardia, hypoplastic optic … (more)
This variant was found once in our laboratory de novo in a newborn female with IUGR, hypotonia, seizures, microcephaly, lissencephaly, cerebellar hypoplasia, tachycardia, hypoplastic optic nerve. (less)
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Pathogenic
(Oct 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Lissencephaly due to TUBA1A mutation
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767149.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with lissencephaly 3 (MIM#611603). Both mechanisms have been reported for missense variants, however dominant negative is the prevalent molecular consequence due to this protein being a heterodimer. Reports found that variants had defects in protein stability and acted dominantly by populating microtubules with defective binding sites for dynein (PMIDs: 20466733, 30517687). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Alternate changes at the same residue, to cysteine and glycine, have previously been reported as pathogenic (ClinVar, Decipher, PMID: 30744660). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in a small number of individuals with lissencephaly 3 (MIM#611603), and is often confirmed to be de novo (ClinVar, PMIDs: 24860126, 30744660). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (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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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 |
Clinical, genetic and neuropathological findings in a series of 138 fetuses with a corpus callosum malformation. | Alby C | Birth defects research. Part A, Clinical and molecular teratology | 2016 | PMID: 26663670 |
Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly. | Fallet-Bianco C | Acta neuropathologica communications | 2014 | PMID: 25059107 |
The wide spectrum of tubulinopathies: what are the key features for the diagnosis? | Bahi-Buisson N | Brain : a journal of neurology | 2014 | PMID: 24860126 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TUBA1A | - | - | - | - |
Text-mined citations for rs886043627 ...
HelpRecord last updated Feb 04, 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.