ClinVar Genomic variation as it relates to human health
NM_006086.4(TUBB3):c.1228G>A (p.Glu410Lys)
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_006086.4(TUBB3):c.1228G>A (p.Glu410Lys)
Variation ID: 6967 Accession: VCV000006967.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q24.3 16: 89935679 (GRCh38) [ NCBI UCSC ] 16: 90002087 (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 5, 2015 Nov 20, 2023 May 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006086.4:c.1228G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006077.2:p.Glu410Lys missense NM_001197181.2:c.1012G>A NP_001184110.1:p.Glu338Lys missense NC_000016.10:g.89935679G>A NC_000016.9:g.90002087G>A NG_027810.1:g.18671G>A Q13509:p.Glu410Lys - Protein change
- E410K, E338K
- Other names
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- Canonical SPDI
- NC_000016.10:89935678:G:A
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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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TUBB3 | No evidence available | No evidence available |
GRCh38 GRCh37 |
288 | 354 |
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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Pathogenic (3) |
no assertion criteria provided
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Aug 12, 2016 | RCV000007382.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2016 | RCV000194090.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 6, 2022 | RCV001539529.12 | |
TUBB3-Releated Disorders
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Pathogenic (1) |
criteria provided, single submitter
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Jun 19, 2019 | RCV001267650.9 |
TUBB3-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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May 10, 2023 | RCV004547462.1 |
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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Pathogenic
(Jun 04, 2015)
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criteria provided, single submitter
Method: clinical testing
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Cortical dysplasia, complex, with other brain malformations 1
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000249307.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Jun 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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TUBB3-Releated Disorders
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001445868.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
This variant has been previously reported as a de novo heterozygous change in patients with hypoplasia of oculomotor nerves, hypoplasia of the corpus callosum, developmental … (more)
This variant has been previously reported as a de novo heterozygous change in patients with hypoplasia of oculomotor nerves, hypoplasia of the corpus callosum, developmental delay, facial weakness, and cyclic vomiting (PMID: 20074521, 23378218, 25559402, 29289389). Functional studies have shown that the c.1228G>A (p.Glu410Lys) variant inhibits axonal transport of vesicles and mitochondria (PMID: 23503589). This variant is in the H12 helix of beta-tubulin and changes the negative charge on the surface of the microtubule, which is important for binding to kinesin superfamily motor proteins (KIFs). The disrupted binding of axonal transport KIFs to microtubules alters the localization of KIFs in neurons and inhibits axon elongation (PMID: 23503589). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1228G>A (p.Glu410Lys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples showed the mother is negative and the father is negative for this variant, indicating this likely occurred as a de novo event. Based on the available evidence, the c.1228G>A (p.Glu410Lys) variant is classified as Pathogenic. (less)
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Pathogenic
(May 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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TUBB3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004104041.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TUBB3 c.1228G>A variant is predicted to result in the amino acid substitution p.Glu410Lys. This variant has been reported to occur de novo in multiple … (more)
The TUBB3 c.1228G>A variant is predicted to result in the amino acid substitution p.Glu410Lys. This variant has been reported to occur de novo in multiple individuals affected by what is known as 'TUBB3 E410K syndrome' (Chew et al. 2013. PubMed ID: 23378218; Romaniello et al. 2017. PubMed ID: 28677066; Tischfield et al. 2010. PubMed ID: 20074521; Grant et al. 2018. PubMed ID: 30272120). Patients were reported to have congenital fibrosis of the extraocular muscles, facial weakness, developmental delay, and possible peripheral neuropathy; however, early signs of this disorder may include fetal distress, stridor, and/or tracheomalacia (Chew et al. 2013. PubMed ID: 23378218). In vitro functional studies indicate that the p.Glu410Lys change significantly inhibits axonal transport of vesicles and mitochondria (Niwa et al. 2013. PubMed ID: 23503589). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret c.1228G>A (p.Glu410Lys) as pathogenic. (less)
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Pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Complex cortical dysplasia with other brain malformations 1
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367774.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2.
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Pathogenic
(Sep 06, 2022)
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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: SCV001757316.3
First in ClinVar: Jul 24, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate E410K affected microtubule polymerization and depolymerization rates as well as kinesin interactions on microtubules and reduced axonal transport of mitochondria in … (more)
Published functional studies demonstrate E410K affected microtubule polymerization and depolymerization rates as well as kinesin interactions on microtubules and reduced axonal transport of mitochondria in peripheral neurons independent of tubulin isoform (Tischfield et al., 2010; Niwa et al., 2013); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29289389, 30272120, 23378218, 25559402, 28299356, 30440138, 29382549, 28677066, 31226147, 20074521, 32573066, 20301522, 20829227, 32005694, 23503589) (less)
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Pathogenic
(Jan 08, 2010)
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no assertion criteria provided
Method: literature only
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FIBROSIS OF EXTRAOCULAR MUSCLES, CONGENITAL, 3A, WITH OR WITHOUT EXTRAOCULAR INVOLVEMENT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027581.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 25, 2016 |
Comment on evidence:
In 6 unrelated individuals with sporadic congenital fibrosis of extraocular muscles-3A (CFEOM3A; 600638), Tischfield et al. (2010) identified a heterozygous 1228G-A transition in exon 4 … (more)
In 6 unrelated individuals with sporadic congenital fibrosis of extraocular muscles-3A (CFEOM3A; 600638), Tischfield et al. (2010) identified a heterozygous 1228G-A transition in exon 4 of the TUBB3 gene, resulting in a glu410-to-lys (E410K) substitution in a region on the external surface of microtubules that mediate interactions with motor proteins and other proteins. All of the mutations appeared to be de novo. In addition to CFEOM, all individuals had developmental delay and facial weakness. Some had agenesis of the corpus callosum on brain MRI. One also had peripheral neuropathy with wrist and finger contractures. In vitro functional expression studies and yeast studies showed that the mutation resulted in decreased polymerization rates and increased depolymerization rates, as well as altered kinesin microtubule interactions. The mutation was not found in over 1,700 control chromosomes. (less)
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Pathogenic
(Aug 12, 2016)
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no assertion criteria provided
Method: research
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Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement
Affected status: yes
Allele origin:
de novo
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CHU Sainte-Justine Research Center, University of Montreal
Accession: SCV000299173.1
First in ClinVar: Sep 04, 2016 Last updated: Sep 04, 2016 |
Comment:
More than 6 individuals described with this mutation, and in vitro functional studies
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not provided
(-)
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no classification provided
Method: literature only
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Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000258990.3
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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Congenital Fibrosis of the Extraocular Muscles Overview. | Adam MP | - | 2021 | PMID: 20301522 |
An exome sequencing study of Moebius syndrome including atypical cases reveals an individual with CFEOM3A and a TUBB3 mutation. | Patel RM | Cold Spring Harbor molecular case studies | 2017 | PMID: 28299356 |
A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3. | Chew S | Brain : a journal of neurology | 2013 | PMID: 23378218 |
Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. | Tischfield MA | Cell | 2010 | PMID: 20074521 |
Text-mined citations for rs267607165 ...
HelpRecord last updated May 27, 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.