ClinVar Genomic variation as it relates to human health
NM_006087.4(TUBB4A):c.763G>A (p.Val255Ile)
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(5); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006087.4(TUBB4A):c.763G>A (p.Val255Ile)
Variation ID: 217025 Accession: VCV000217025.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.3 19: 6495736 (GRCh38) [ NCBI UCSC ] 19: 6495747 (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 Oct 11, 2015 Apr 6, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006087.4:c.763G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006078.2:p.Val255Ile missense NM_001289123.1:c.916G>A NM_001289123.2:c.916G>A NP_001276052.1:p.Val306Ile missense NM_001289127.2:c.898G>A NP_001276056.1:p.Val300Ile missense NM_001289129.2:c.763G>A NP_001276058.1:p.Val255Ile missense NM_001289130.2:c.547G>A NP_001276059.1:p.Val183Ile missense NM_001289131.2:c.547G>A NP_001276060.1:p.Val183Ile missense NC_000019.10:g.6495736C>T NC_000019.9:g.6495747C>T NG_033896.1:g.12113G>A - Protein change
- V255I, V306I, V300I, V183I
- Other names
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- Canonical SPDI
- NC_000019.10:6495735: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
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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TUBB4A | No evidence available | No evidence available |
GRCh38 GRCh37 |
281 | 308 |
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
Help
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 (5) |
criteria provided, conflicting classifications
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Mar 26, 2024 | RCV000199587.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 17, 2021 | RCV000290772.4 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001004001.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 4, 2021 | RCV002515471.1 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001527369.2 |
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
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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
(Apr 02, 2013)
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criteria provided, single submitter
Method: clinical testing
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Leukodystrophy, hypomyelinating, 6
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255501.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Age: 0-9 years
Sex: female
Ethnicity/Population group: Asian
Testing laboratory: UCLA Clinical Genomics Center
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Hypomyelinating leukodystrophy 6
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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TIDEX, University of British Columbia
Accession: SCV000586833.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
Sex: male
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Microcephaly
Affected status: yes
Allele origin:
de novo
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Bicknell laboratory, University of Otago
Accession: SCV001738351.1
First in ClinVar: Jun 25, 2021 Last updated: Jun 25, 2021 |
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Pathogenic
(Jun 17, 2021)
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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: SCV001761992.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Global developmental delay (present) , Cerebellar atrophy (present)
Sex: female
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Pathogenic
(May 18, 2021)
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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: SCV000329904.6
First in ClinVar: Dec 06, 2016 Last updated: Dec 19, 2017 |
Comment:
Published functional studies demonstrate a damaging effect with significant reduction in tubulin polymerization and altered ability to incorporate into microtubules, suggestive of a toxic dominant … (more)
Published functional studies demonstrate a damaging effect with significant reduction in tubulin polymerization and altered ability to incorporate into microtubules, suggestive of a toxic dominant gain-of-function mechanism (Curiel et al, 2017); Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26934450, 25326637, 25085639, 27809427, 28973395, 32581362, 30542205) (less)
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Likely pathogenic
(Jun 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003564336.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.763G>A (p.V255I) alteration is located in exon 4 (coding exon 4) of the TUBB4A gene. This alteration results from a G to A substitution … (more)
The c.763G>A (p.V255I) alteration is located in exon 4 (coding exon 4) of the TUBB4A gene. This alteration results from a G to A substitution at nucleotide position 763, causing the valine (V) at amino acid position 255 to be replaced by an isoleucine (I). Based on data from the Genome Aggregation Database (gnomAD), the TUBB4A c.763G>A alteration was not observed, with coverage at this position. This alteration was reported de novo in a 5 year old girl with spastic quadriparesis, hypotonia, ataxia, developmental delay, and a brain MRI showing hypomyelination and mild cerebellar vermis atrophy (Pizzino, 2014). This alteration was reported de novo in another patient with developmental delay, microcephaly, truncal hypotonia, limb hypertonia, foot clonus, and cerebellar hypoplasia/atrophy (Lee, 2014). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Histo-pathological examination of brain tissue from affected individuals with the p.V255I alteration showed abnormal morphology of oligodendrocytes, and in vitro functional studies showed decreased tubulin polymerization and decreased myelin protein expression (Curiel, 2017). The p.V255I alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 04, 2023)
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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: SCV000828297.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 255 of the TUBB4A protein (p.Val255Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 255 of the TUBB4A protein (p.Val255Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dystonia, isolated hypomyelination, or dystonia with hypomyelinating leukodystrophy (PMID: 25085639, 25326637; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217025). 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 TUBB4A protein function. Experimental studies have shown that this missense change affects TUBB4A function (PMID: 28973395). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Mar 26, 2024)
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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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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807039.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Cerebral palsy
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162045.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: male
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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: SCV000328466.2
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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Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
TUBB4A mutations result in specific neuronal and oligodendrocytic defects that closely match clinically distinct phenotypes. | Curiel J | Human molecular genetics | 2017 | PMID: 28973395 |
TUBB4A-Related Leukodystrophy. | Adam MP | - | 2016 | PMID: 27809427 |
Clinical exome sequencing for genetic identification of rare Mendelian disorders. | Lee H | JAMA | 2014 | PMID: 25326637 |
TUBB4A de novo mutations cause isolated hypomyelination. | Pizzino A | Neurology | 2014 | PMID: 25085639 |
Text-mined citations for rs767399782 ...
HelpRecord last updated Apr 06, 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.