ClinVar Genomic variation as it relates to human health
NM_006087.4(TUBB4A):c.5G>A (p.Arg2Gln)
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_006087.4(TUBB4A):c.5G>A (p.Arg2Gln)
Variation ID: 139452 Accession: VCV000139452.76
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.3 19: 6502208 (GRCh38) [ NCBI UCSC ] 19: 6502219 (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 Jun 27, 2015 Feb 14, 2024 Sep 1, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006087.4:c.5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006078.2:p.Arg2Gln missense NM_001289123.2:c.158G>A NP_001276052.1:p.Arg53Gln missense NM_001289127.2:c.140G>A NP_001276056.1:p.Arg47Gln missense NM_001289129.2:c.5G>A NP_001276058.1:p.Arg2Gln missense NM_001289130.2:c.-169G>A 5 prime UTR NM_001289131.2:c.-136G>A 5 prime UTR NC_000019.10:g.6502208C>T NC_000019.9:g.6502219C>T NG_033896.1:g.5641G>A - Protein change
- R2Q, R53Q, R47Q
- Other names
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- Canonical SPDI
- NC_000019.10:6502207: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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TUBB4A | No evidence available | No evidence available |
GRCh38 GRCh37 |
282 | 309 | |
LOC130063295 | - | - | - | GRCh38 | - | 17 |
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
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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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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2022 | RCV000128409.24 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 23, 2017 | RCV000350313.9 |
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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Pathogenic
(Oct 23, 2019)
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criteria provided, single submitter
Method: clinical testing
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Leukodystrophy, hypomyelinating, 6
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV001423765.2
First in ClinVar: Jul 27, 2020 Last updated: Mar 04, 2023 |
Comment:
The TUBB4A c.5G>A (p.Arg2Gln) missense variant (also known as c.158G>A; p.Arg53Gln) has been reported in two studies in which it is identified in a heterozygous … (more)
The TUBB4A c.5G>A (p.Arg2Gln) missense variant (also known as c.158G>A; p.Arg53Gln) has been reported in two studies in which it is identified in a heterozygous state in two individuals (Hamilton et al. 2014; Miyatake et al. 2014). Hamilton et al. (2014) identified the p.Arg2Gln variant in a presumed de novo state in a non-ambulatory 18 year-old female with nystagmus, intellectual disability, absent speech, g-tube dependent feeding, and abnormal MRI findings including an initially normal putamen and an almost complete lack of myelin. Miyatake et al. (2014) identified the p.Arg2Gln variant in a heterozygous state in a 15-year-old girl with severe intellectual disability, no head control, spasticity, rigidity, choreoathetosis, dystonia and MRI findings consistent with hypomyelinating leukodystrophy. Parental samples were not available for testing. Two additional patients with hypomyelination with atrophy of the basal ganglia and cerebellum with different missense variants at the same residue are also reported (Hamilton et al. 2014). The p.Arg2Gln variant was absent from 575 controls subjects (Miyatake et al. 2014) and is not found in the Genome Aggregation Database in a region of good sequence coverage. The p.Arg2Gln variant occurs within the MREI motif which is involved in autoregulatory mechanisms for beta-tubulin stability (Hersheson et al. 2013). Based on the available evidence and the application of the ACMG criteria, the p.Arg2Gln variant is classified as pathogenic for TUBB4A-related leukodystrophy. (less)
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Pathogenic
(Jul 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypomyelinating leukodystrophy 6
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002129845.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant disrupts the p.Arg2 amino acid residue in TUBB4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23595291). This … (more)
This variant disrupts the p.Arg2 amino acid residue in TUBB4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23595291). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TUBB4A protein function (PMID: 3405308). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 139452). This variant has been observed in individual(s) with clinical features of hypomyelinating leukodystrophy (PMID: 24785942, 24850488). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 2 of the TUBB4A protein (p.Arg2Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. (less)
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Pathogenic
(Mar 23, 2017)
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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: SCV000329905.6
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The R2Q pathogenic variant in the TUBB4A gene has been reported multiple times previously in assocation with atrophy of the basal ganglia and cerebellum (H-ABC) … (more)
The R2Q pathogenic variant in the TUBB4A gene has been reported multiple times previously in assocation with atrophy of the basal ganglia and cerebellum (H-ABC) (Miyatake et al., 2014; Hamilton et al., 2014). Additionally, missense variants in the same residue but involving different amino acid substitutions (R2W and R2G) have been reported in association with H-ABC and dystonia type 4 respectively (Hamilton et al., 2014; Hersheson et al., 2013). The R2Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R2Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a highly conserved position within the beta-tubulin tetrapeptide Met-Arg-Glu-Ile (MREI) motif which is involved in autoregulatory mechanisms for beta-tubulin stability (Miyatake et al., 2014). (less)
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: research
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Hypomyelinating leukodystrophy 6
(Sporadic)
Affected status: yes
Allele origin:
de novo
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MyeliNeuroGene Lab, McGill University Health Center Research Institute
Accession: SCV002820979.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Number of individuals with the variant: 1
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Pathogenic
(May 21, 2014)
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no assertion criteria provided
Method: literature only
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LEUKODYSTROPHY, HYPOMYELINATING, 6
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000172073.4
First in ClinVar: Jun 23, 2014 Last updated: Nov 11, 2023 |
Comment on evidence:
In a 15-year-old Japanese girl with hypomyelinating leukodystrophy-6 (HLD6; 612438), Miyatake et al. (2014) identified a heterozygous c.5G-A transition in the TUBB4A gene, resulting in … (more)
In a 15-year-old Japanese girl with hypomyelinating leukodystrophy-6 (HLD6; 612438), Miyatake et al. (2014) identified a heterozygous c.5G-A transition in the TUBB4A gene, resulting in an arg2-to-gln (R2Q) substitution at a highly conserved residue in the MREI motif involved in autoregulatory mechanisms for beta-tubulin stability. The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. Parental DNA was not available. Structural modeling showed that the R2Q substitution occurs at an intraheterodimer interface, suggesting that the mutation may affect tubulin heterodimerization; however, functional studies were not performed. The patient had a severe disorder, with onset of symptoms at 1.5 months of age. She had severe mental retardation with no head control, spasticity, rigidity, choreoathetosis, and dystonia. Brain MRI showed hypomyelination and atrophy of the cerebellum, basal ganglia, and corpus callosum. Miyatake et al. (2014) noted that a mutation at the same residue (R2G; 602662.0001) had been reported in a single large family with a much milder and different phenotype (DYT4; 128101), and Miyatake et al. (2014) suggested that the large DYT4 family may have another modifying factor that protects against white matter abnormalities. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Hypomyelinating leukodystrophy 6
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000328457.2
First in ClinVar: Oct 11, 2015 Last updated: Oct 01, 2022 |
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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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TUBB4A-Related Leukodystrophy. | Adam MP | - | 2016 | PMID: 27809427 |
Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies. | Miyatake S | Neurology | 2014 | PMID: 24850488 |
Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation. | Hamilton EM | Brain : a journal of neurology | 2014 | PMID: 24785942 |
Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene. | Lohmann K | Annals of neurology | 2013 | PMID: 23595291 |
Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia. | Hersheson J | Annals of neurology | 2013 | PMID: 23424103 |
Autoregulated instability of beta-tubulin mRNAs by recognition of the nascent amino terminus of beta-tubulin. | Yen TJ | Nature | 1988 | PMID: 3405308 |
Text-mined citations for rs587777467 ...
HelpRecord last updated May 01, 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.