ClinVar Genomic variation as it relates to human health
NM_006086.4(TUBB3):c.784C>T (p.Arg262Cys)
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.784C>T (p.Arg262Cys)
Variation ID: 6963 Accession: VCV000006963.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q24.3 16: 89935235 (GRCh38) [ NCBI UCSC ] 16: 90001643 (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 Feb 14, 2024 Jun 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006086.4:c.784C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006077.2:p.Arg262Cys missense NM_001197181.2:c.568C>T NP_001184110.1:p.Arg190Cys missense NC_000016.10:g.89935235C>T NC_000016.9:g.90001643C>T NG_027810.1:g.18227C>T Q13509:p.Arg262Cys - Protein change
- R262C, R190C
- Other names
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- Canonical SPDI
- NC_000016.10:89935234: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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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
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
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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) |
criteria provided, single submitter
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Feb 2, 2022 | RCV000007378.15 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 20, 2023 | RCV000254974.16 |
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
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557690.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with congenital fibrosis of extraocular muscles 3A (MIM#600638) (PMID: 31219644). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent pathogenic variant associated with the milder form of congenital fibrosis of extraocular muscles (ClinVar, PMID: 20074521, 32573066). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Mar 28, 2023)
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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: SCV000322100.8
First in ClinVar: Oct 09, 2016 Last updated: Apr 09, 2023 |
Comment:
Reported in unrelated patients with TUBB3-related CFEOM referred for genetic testing at GeneDx and in the published literature (Tischfield et al., 2010); Published functional studies … (more)
Reported in unrelated patients with TUBB3-related CFEOM referred for genetic testing at GeneDx and in the published literature (Tischfield et al., 2010); Published functional studies demonstrate impaired microtubule function (Tischfield et al., 2010); 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); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28832562, 27428177, 29382549, 31226147, 20074521, 29453417, 24077912) (less)
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Pathogenic
(Jun 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
maternal
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026432.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PS3, PP4, PP3, PM5, PS4, PM2_SUP
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Pathogenic
(May 03, 2021)
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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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Invitae
Accession: SCV002126632.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects TUBB3 protein function (PMID: 20074521). This variant … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects TUBB3 protein function (PMID: 20074521). This variant has been observed in individual(s) with congenital fibrosis of the extraocular muscles type 3 (PMID: 20074521, 29453417). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg190Cys. ClinVar contains an entry for this variant (Variation ID: 6963). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 262 of the TUBB3 protein (p.Arg262Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. (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: SCV000027577.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 25, 2016 |
Comment on evidence:
In affected members of 11 unrelated pedigrees with congenital fibrosis of extraocular muscles-3A (CFEOM3A; 600638), Tischfield et al. (2010) identified a heterozygous 784C-T transition in … (more)
In affected members of 11 unrelated pedigrees with congenital fibrosis of extraocular muscles-3A (CFEOM3A; 600638), Tischfield et al. (2010) identified a heterozygous 784C-T transition in exon 4 of the TUBB3 gene, resulting in an arg262-to-cys (R262C) substitution. Several of the pedigrees had previously been reported by Doherty et al. (1999), Gillies et al. (1995), Mackey et al. (2002), and Yamada et al. (2004). The ocular motility defects ranged from severe to mild. Brain MRI of affected members in 4 pedigrees showed hypoplasia of the oculomotor nerve and the muscles innervated by its superior division, the levator palpebrae superioris and superior rectus, as well as the medial rectus muscle innervated by its inferior division. The oculomotor nerve also aberrantly innervated the lateral rectus muscle, normally innervated by the abducens nerve. The findings were consistent with axon guidance defects. In addition, affected individuals in some of the families showed developmental delay or learning disabilities, and some had mild dysgenesis of the corpus callosum. In vitro studies showed patchy mutant heterodimer incorporation into microtubules. Further studies showed decreased polymerization rates and increased depolymerization rates, as well as altered interaction with kinesins. The mutation was not found in over 1,700 control chromosomes. (less)
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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: SCV000258986.3
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 |
TUBB3 E410K syndrome: Case report and review of the clinical spectrum of TUBB3 mutations. | Dentici ML | American journal of medical genetics. Part A | 2020 | PMID: 32573066 |
The role of protein complexes in human genetic disease. | Bergendahl LT | Protein science : a publication of the Protein Society | 2019 | PMID: 31219644 |
Exome sequencing has higher diagnostic yield compared to simulated disease-specific panels in children with suspected monogenic disorders. | Dillon OJ | European journal of human genetics : EJHG | 2018 | PMID: 29453417 |
Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. | Tischfield MA | Cell | 2010 | PMID: 20074521 |
Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3). | Yamada K | Investigative ophthalmology & visual science | 2004 | PMID: 15223798 |
Congenital fibrosis of the vertically acting extraocular muscles maps to the FEOM3 locus. | Mackey DA | Human genetics | 2002 | PMID: 12073023 |
CFEOM3: a new extraocular congenital fibrosis syndrome that maps to 16q24.2-q24.3. | Doherty EJ | Investigative ophthalmology & visual science | 1999 | PMID: 10393037 |
Congenital fibrosis of the vertically acting extraocular muscles. A new group of dominantly inherited ocular fibrosis with radiologic findings. | Gillies WE | Ophthalmology | 1995 | PMID: 7724178 |
Text-mined citations for rs267607162 ...
HelpRecord last updated Jun 10, 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.