Analysis of the exome sequencing data showed a heterozygous sequence variant in TUBA1A gene. This variant is predicted as Disease Causing by MutationTaster. Sanger sequencing confirmed the variation in the proband. Parents were homozygous for the wildtype allele.
ClinVar Genomic variation as it relates to human health
NM_006009.4(TUBA1A):c.1265G>A (p.Arg422His)
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.
(10)
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
10
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.1265G>A (p.Arg422His)
Variation ID: 7077 Accession: VCV000007077.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q13.12 12: 49185101 (GRCh38) [ NCBI UCSC ] 12: 49578884 (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 Feb 14, 2024 Jun 3, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006009.4:c.1265G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006000.2:p.Arg422His missense NM_001270399.2:c.1265G>A NP_001257328.1:p.Arg422His missense NM_001270400.2:c.1160G>A NP_001257329.1:p.Arg387His missense NC_000012.12:g.49185101C>T NC_000012.11:g.49578884C>T NG_008966.1:g.8978G>A - Protein change
- R422H, R387H
- Other names
- -
- Canonical SPDI
- NC_000012.12:49185100:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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 |
371 | 382 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Feb 8, 2013 | RCV000007493.15 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 3, 2022 | RCV000255074.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 1, 2018 | RCV000767410.5 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001291201.4 |
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
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
(Feb 08, 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: SCV000195272.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Lissencephaly due to TUBA1A mutation
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences
Accession: SCV001451922.1
First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021 |
Comment:
Analysis of the exome sequencing data showed a heterozygous sequence variant in TUBA1A gene. This variant is predicted as Disease Causing by MutationTaster. Sanger sequencing … (more)
Analysis of the exome sequencing data showed a heterozygous sequence variant in TUBA1A gene. This variant is predicted as Disease Causing by MutationTaster. Sanger sequencing confirmed the variation in the proband. Parents were homozygous for the wildtype allele. (less)
Clinical Features:
Microcephaly (present) , Lissencephaly (present) , Seizure (present) , Sloping forehead (present) , Highly arched eyebrow (present) , Global developmental delay (present)
Age: 0-9 years
Sex: male
Ethnicity/Population group: North Indian
Geographic origin: India
|
|
|
Pathogenic
(Oct 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321986.8
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in … (more)
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21875651, 25059107, 24860126, 22264709, 18669490, 29671837, 20466733, 26350204, 18954413, 20376468, 22948023, 18728072, 33453472, 30744660) (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: not provided
|
Lissencephaly due to TUBA1A mutation
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Accession: SCV004037187.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Clinical Features:
Microcephaly (present) , Infantile spasms (present) , Lissencephaly (present) , Corpus callosum, agenesis of (present) , Hypotonia (present) , Global developmental delay (present) , Autosomal … (more)
Microcephaly (present) , Infantile spasms (present) , Lissencephaly (present) , Corpus callosum, agenesis of (present) , Hypotonia (present) , Global developmental delay (present) , Autosomal dominant inheritance (present) (less)
|
|
|
Pathogenic
(Jun 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002148511.3
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.Arg422 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.Arg422 amino acid residue in TUBA1A. Other variant(s) that disrupt this residue have been observed in individuals with TUBA1A-related conditions (PMID: 18728072), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 7077). This missense change has been observed in individual(s) with cortical malformations (PMID: 18728072, 20466733, 26350204, 29671837). 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 422 of the TUBA1A protein (p.Arg422His). (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: SCV000898025.1
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 9 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 9 years old born individual of male sex. The c.1265G>A, p.(Arg422His) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Morris-Rosendahl et al. Clin Genet, 2008 PMID: 18954413. HPO-standardized clinical features were: Partial agenesis of the corpus callosum (HP:0001338); Pachygyria (HP:0001302); Cerebellar vermis hypoplasia (HP:0001320); Hypoplasia of the pons (HP:0012110); Dysgenesis of the hippocampus (HP:0025101); Dilation of lateral ventricles, Dilated fourth ventricle (HP:0006956, HP:0002198); Gray matter heterotopia (HP:0002281); Congenital microcephaly (HP:0011451); Microcephaly (HP:0000252); Muscular hypotonia (HP:0001252); Generalized tonic-clonic seizures (HP:0002069) (less)
Number of individuals with the variant: 4
Age: 0-9 years
Sex: male
Ethnicity/Population group: Portuguese
|
|
|
Pathogenic
(Nov 01, 2008)
|
no assertion criteria provided
Method: literature only
|
LISSENCEPHALY 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027693.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 16, 2021 |
Comment on evidence:
In 2 unrelated patients with lissencephaly-3 (LIS3; 611603), Morris-Rosendahl et al. (2008) identified a heterozygous 1265G-A transition in exon 4 of the TUBA1A gene, resulting … (more)
In 2 unrelated patients with lissencephaly-3 (LIS3; 611603), Morris-Rosendahl et al. (2008) identified a heterozygous 1265G-A transition in exon 4 of the TUBA1A gene, resulting in an arg422-to-his (R422H) substitution. In addition to the classic features of microcephaly, seizure, pachygyria, and hypoplasia of the corpus callosum and cerebellum, both patients had subtle evidence of subcortical band heterotopia. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Lissencephaly due to TUBA1A mutation
Affected status: yes
Allele origin:
unknown
|
Service de Génétique Moléculaire, Hôpital Robert Debré
Accession: SCV001432345.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
|
|
|
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: SCV001479626.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Lissencephaly type 3
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000266414.2
First in ClinVar: Mar 29, 2016 Last updated: Oct 01, 2022 |
Comment:
Classic lissencephaly
|
Comment:
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21875651, 25059107, 24860126, 22264709, 18669490, 29671837, 20466733, 26350204, 18954413, 20376468, 22948023, 18728072, 33453472, 30744660)
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg422 amino acid residue in TUBA1A. Other variant(s) that disrupt this residue have been observed in individuals with TUBA1A-related conditions (PMID: 18728072), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 7077). This missense change has been observed in individual(s) with cortical malformations (PMID: 18728072, 20466733, 26350204, 29671837). 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 422 of the TUBA1A protein (p.Arg422His).
Comment:
A variant that is classified as pathogenic has been identified in the TUBA1A gene in a 9 years old born individual of male sex. The c.1265G>A, p.(Arg422His) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Morris-Rosendahl et al. Clin Genet, 2008 PMID: 18954413. HPO-standardized clinical features were: Partial agenesis of the corpus callosum (HP:0001338); Pachygyria (HP:0001302); Cerebellar vermis hypoplasia (HP:0001320); Hypoplasia of the pons (HP:0012110); Dysgenesis of the hippocampus (HP:0025101); Dilation of lateral ventricles, Dilated fourth ventricle (HP:0006956, HP:0002198); Gray matter heterotopia (HP:0002281); Congenital microcephaly (HP:0011451); Microcephaly (HP:0000252); Muscular hypotonia (HP:0001252); Generalized tonic-clonic seizures (HP:0002069)
Comment:
Classic lissencephaly
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. |
Comment:
Analysis of the exome sequencing data showed a heterozygous sequence variant in TUBA1A gene. This variant is predicted as Disease Causing by MutationTaster. Sanger sequencing confirmed the variation in the proband. Parents were homozygous for the wildtype allele.
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21875651, 25059107, 24860126, 22264709, 18669490, 29671837, 20466733, 26350204, 18954413, 20376468, 22948023, 18728072, 33453472, 30744660)
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg422 amino acid residue in TUBA1A. Other variant(s) that disrupt this residue have been observed in individuals with TUBA1A-related conditions (PMID: 18728072), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 7077). This missense change has been observed in individual(s) with cortical malformations (PMID: 18728072, 20466733, 26350204, 29671837). 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 422 of the TUBA1A protein (p.Arg422His).
Comment:
A variant that is classified as pathogenic has been identified in the TUBA1A gene in a 9 years old born individual of male sex. The c.1265G>A, p.(Arg422His) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Morris-Rosendahl et al. Clin Genet, 2008 PMID: 18954413. HPO-standardized clinical features were: Partial agenesis of the corpus callosum (HP:0001338); Pachygyria (HP:0001302); Cerebellar vermis hypoplasia (HP:0001320); Hypoplasia of the pons (HP:0012110); Dysgenesis of the hippocampus (HP:0025101); Dilation of lateral ventricles, Dilated fourth ventricle (HP:0006956, HP:0002198); Gray matter heterotopia (HP:0002281); Congenital microcephaly (HP:0011451); Microcephaly (HP:0000252); Muscular hypotonia (HP:0001252); 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 |
| 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 |
| Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability. | Grozeva D | Human mutation | 2015 | PMID: 26350204 |
| 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 |
| Refining the phenotype of alpha-1a Tubulin (TUBA1A) mutation in patients with classical lissencephaly. | Morris-Rosendahl DJ | Clinical genetics | 2008 | PMID: 18954413 |
| Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations. | Bahi-Buisson N | Journal of medical genetics | 2008 | PMID: 18728072 |
Text-mined citations for rs137853050 ...
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 Sep 29, 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.