This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
ClinVar Genomic variation as it relates to human health
NM_001069.3(TUBB2A):c.292G>A (p.Gly98Arg)
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.
(9)
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/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001069.3(TUBB2A):c.292G>A (p.Gly98Arg)
Variation ID: 421739 Accession: VCV000421739.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p25.2 6: 3154909 (GRCh38) [ NCBI UCSC ] 6: 3155143 (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 Dec 19, 2017 Mar 23, 2024 Dec 2, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001069.3:c.292G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001060.1:p.Gly98Arg missense NM_001310315.2:c.37G>A NP_001297244.1:p.Gly13Arg missense NC_000006.12:g.3154909C>T NC_000006.11:g.3155143C>T NG_042223.1:g.7641G>A - Protein change
- G98R, G13R
- Other names
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- Canonical SPDI
- NC_000006.12:3154908: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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
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| TUBB2A | - | - |
GRCh38 GRCh37 |
297 | 376 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 2, 2023 | RCV000480960.9 | |
| Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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May 27, 2020 | RCV000824991.12 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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Oct 27, 2019 | RCV003985086.1 |
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
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. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Oct 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Complex cortical dysplasia with other brain malformations 5
Affected status: yes
Allele origin:
de novo
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000966174.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
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Likely pathogenic
(Jul 10, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Complex cortical dysplasia with other brain malformations 5
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149976.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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Likely pathogenic
(May 27, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Complex cortical dysplasia with other brain malformations 5
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001525133.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
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Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Complex cortical dysplasia with other brain malformations 5
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073048.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Comment:
The missense variant p.G98R in TUBB2A (NM_001069.3) has been previously reported as a de novo variant in 3 unrelated affected individuals with global developmental delay, … (more)
The missense variant p.G98R in TUBB2A (NM_001069.3) has been previously reported as a de novo variant in 3 unrelated affected individuals with global developmental delay, seizures and cortical malformations (Schmidt L et al, 2021). The variant has been submitted to ClinVar as Likely Pathogenic. The variant is novel (not in any individuals) in gnomAD Exomes.The p.G98R variant is novel (not in any individuals) in 1000 Genomes. The p.G98R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 98 of TUBB2A is conserved in all mammalian species. The nucleotide c.292 in TUBB2A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Dystonic disorder (present)
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Pathogenic
(Nov 24, 2021)
|
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: SCV000571035.6
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33776625, 33064843) (less)
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Pathogenic
(Dec 02, 2023)
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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: SCV003518982.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 98 of the TUBB2A protein (p.Gly98Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 98 of the TUBB2A protein (p.Gly98Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cortical malformations (PMID: 33776625). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421739). 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 TUBB2A protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Tubulinopathy
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004801612.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The TUBB2A c.292G>A p.(Gly98Arg) missense variant has not, to our knowledge, been reported in the peer-reviewed literature in association with tubulinopathy. However, the corresponding variant … (more)
The TUBB2A c.292G>A p.(Gly98Arg) missense variant has not, to our knowledge, been reported in the peer-reviewed literature in association with tubulinopathy. However, the corresponding variant in the highly homologous (98% amino-acid sequence homology) TUBB2B gene, p.(Gly98Arg), has been reported in a heterozygous de novo state in at least two individuals with a tubulinopathy phenotype (Cushion et al. 2013; Bahi-Buisson et al. 2014). The TUBB2A p.Gly98Arg variant is not observed in version 2.1.1 of the Genome Aggregation Database. The variant was identified in a de novo state in the proband. Based on the available evidence the c.292G>A p.(Gly98Arg) variant is classified as likely pathogenic for tubulinopathy. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Complex cortical dysplasia with other brain malformations 5
Affected status: yes
Allele origin:
unknown
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Service de Génétique Moléculaire, Hôpital Robert Debré
Accession: SCV001432472.1
First in ClinVar: Sep 16, 2020 Last updated: Sep 16, 2020 |
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Pathogenic
(Sep 23, 2021)
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no assertion criteria provided
Method: literature only
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CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001934601.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Comment on evidence:
In 3 unrelated patients with complex cortical dysplasia with other brain malformations-5 (CDCBM5; 615763), Schmidt et al. (2021) identified a de novo heterozygous c.292G-A transition … (more)
In 3 unrelated patients with complex cortical dysplasia with other brain malformations-5 (CDCBM5; 615763), Schmidt et al. (2021) identified a de novo heterozygous c.292G-A transition (c.292G-A, NM_001069.2) in the TUBB2A gene, resulting in a gly98-to-arg (G98R) substitution at a conserved residue. The mutation was identified by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing. The mutation was not present in the gnomAD database. Functional studies were not performed. (less)
|
Comment:
Comment:
The missense variant p.G98R in TUBB2A (NM_001069.3) has been previously reported as a de novo variant in 3 unrelated affected individuals with global developmental delay, seizures and cortical malformations (Schmidt L et al, 2021). The variant has been submitted to ClinVar as Likely Pathogenic. The variant is novel (not in any individuals) in gnomAD Exomes.The p.G98R variant is novel (not in any individuals) in 1000 Genomes. The p.G98R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 98 of TUBB2A is conserved in all mammalian species. The nucleotide c.292 in TUBB2A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33776625, 33064843)
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 98 of the TUBB2A protein (p.Gly98Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cortical malformations (PMID: 33776625). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421739). 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 TUBB2A protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Comment:
The TUBB2A c.292G>A p.(Gly98Arg) missense variant has not, to our knowledge, been reported in the peer-reviewed literature in association with tubulinopathy. However, the corresponding variant in the highly homologous (98% amino-acid sequence homology) TUBB2B gene, p.(Gly98Arg), has been reported in a heterozygous de novo state in at least two individuals with a tubulinopathy phenotype (Cushion et al. 2013; Bahi-Buisson et al. 2014). The TUBB2A p.Gly98Arg variant is not observed in version 2.1.1 of the Genome Aggregation Database. The variant was identified in a de novo state in the proband. Based on the available evidence the c.292G>A p.(Gly98Arg) variant is classified as likely pathogenic for tubulinopathy.
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:
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
The missense variant p.G98R in TUBB2A (NM_001069.3) has been previously reported as a de novo variant in 3 unrelated affected individuals with global developmental delay, seizures and cortical malformations (Schmidt L et al, 2021). The variant has been submitted to ClinVar as Likely Pathogenic. The variant is novel (not in any individuals) in gnomAD Exomes.The p.G98R variant is novel (not in any individuals) in 1000 Genomes. The p.G98R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 98 of TUBB2A is conserved in all mammalian species. The nucleotide c.292 in TUBB2A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33776625, 33064843)
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 98 of the TUBB2A protein (p.Gly98Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cortical malformations (PMID: 33776625). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421739). 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 TUBB2A protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Comment:
The TUBB2A c.292G>A p.(Gly98Arg) missense variant has not, to our knowledge, been reported in the peer-reviewed literature in association with tubulinopathy. However, the corresponding variant in the highly homologous (98% amino-acid sequence homology) TUBB2B gene, p.(Gly98Arg), has been reported in a heterozygous de novo state in at least two individuals with a tubulinopathy phenotype (Cushion et al. 2013; Bahi-Buisson et al. 2014). The TUBB2A p.Gly98Arg variant is not observed in version 2.1.1 of the Genome Aggregation Database. The variant was identified in a de novo state in the proband. Based on the available evidence the c.292G>A p.(Gly98Arg) variant is classified as likely pathogenic for tubulinopathy.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Expanding the Phenotype of TUBB2A-Related Tubulinopathy: Three Cases of a Novel, Heterozygous TUBB2A Pathogenic Variant p.Gly98Arg. | Schmidt L | Molecular syndromology | 2021 | PMID: 33776625 |
Text-mined citations for rs1064795334 ...
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.