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NM_178012.5(TUBB2B):c.1261G>A (p.Glu421Lys) AND Complex cortical dysplasia with other brain malformations 7

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Dec 15, 2012
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000074466.12

Allele description [Variation Report for NM_178012.5(TUBB2B):c.1261G>A (p.Glu421Lys)]

NM_178012.5(TUBB2B):c.1261G>A (p.Glu421Lys)

Gene:
TUBB2B:tubulin beta 2B class IIb [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6p25.2
Genomic location:
Preferred name:
NM_178012.5(TUBB2B):c.1261G>A (p.Glu421Lys)
HGVS:
  • NC_000006.12:g.3224828C>T
  • NG_016715.1:g.7907G>A
  • NM_178012.5:c.1261G>AMANE SELECT
  • NP_821080.1:p.Glu421Lys
  • NC_000006.11:g.3225062C>T
  • NM_178012.4:c.1261G>A
Protein change:
E421K; GLU421LYS
Links:
OMIM: 612850.0007; dbSNP: rs398122369
NCBI 1000 Genomes Browser:
rs398122369
Molecular consequence:
  • NM_178012.5:c.1261G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Complex cortical dysplasia with other brain malformations 7
Synonyms:
Polymicrogyria, asymmetric
Identifiers:
MONDO: MONDO:0012399; MedGen: C3552236; Orphanet: 300573; OMIM: 610031

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000108482OMIM
no assertion criteria provided
Pathogenic
(Dec 15, 2012)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000258993GeneReviews
no classification provided
not providedgermlineliterature only

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineyesnot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Congenital fibrosis of the extraocular muscles associated with cortical dysplasia and maldevelopment of the basal ganglia.

Flaherty MP, Grattan-Smith P, Steinberg A, Jamieson R, Engle EC.

Ophthalmology. 2001 Jul;108(7):1313-22.

PubMed [citation]
PMID:
11425694

An inherited TUBB2B mutation alters a kinesin-binding site and causes polymicrogyria, CFEOM and axon dysinnervation.

Cederquist GY, Luchniak A, Tischfield MA, Peeva M, Song Y, Menezes MP, Chan WM, Andrews C, Chew S, Jamieson RV, Gomes L, Flaherty M, Grant PE, Gupta ML Jr, Engle EC.

Hum Mol Genet. 2012 Dec 15;21(26):5484-99. doi: 10.1093/hmg/dds393. Epub 2012 Sep 21.

PubMed [citation]
PMID:
23001566
PMCID:
PMC3516133

Details of each submission

From OMIM, SCV000108482.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

In a mother and her 2 daughters with complex cortical dysplasia with other brain malformations-7 (CDCBM7; 610031) manifest as diffuse symmetric polymicrogyria, originally reported by Flaherty et al. (2001), Cederquist et al. (2012) identified a heterozygous c.1261G-A transition in exon 4 of the TUBB2B gene, resulting in a glu421-to-lys (E421K) substitution at a highly conserved residue in the C-terminal H12 alpha-helix of the protein crucial for kinesin-microtubule interactions. The mutation was not present in the dbSNP, 1000 Genomes, or Exome Variant Server databases, and was not found in 336 control individuals. The patients had intellectual impairment and congenital fibrosis of the extraocular muscles associated with hypoplasia of the extraocular muscles apparent in brain MRI. Brain MRI also showed polymicrogyria, asymmetry of the basal ganglia and ventricles, and thin corpus callosum. Diffusion tensor imaging of both daughters showed abnormal intracortical homotopic connectivity in the corpus callosum. Transfection of the mutation into wildtype callosal projection neurons of embryonic mice caused a decrease in the ratio of contralateral to ipsilateral tracts, consistent with an error in axonal pathfinding and targeted innervation, but this was not secondary to cortical dysplasia. Overexpression of the E421K mutant protein perturbed the accuracy of both local and long-range projections. Mutant E421K was able to assemble into alpha-beta heterodimers, although with slightly less efficiency compared to wildtype, and the mutant protein incorporated into microtubule networks. Studies in yeast showed that the mutation affected microtubule dynamics in a dominant manner, causing increased overall stability, and also altered kinesin (KIP3; 610645) localization. The findings were consistent with primary axonal dysinnervation. Cederquist et al. (2012) noted that similar mutations in the TUBB3 gene (D417N; 602661.0004 and E410K; 602661.0005) cause CFEOM3A (600638); these mutations also alter microtubule dynamics and interactions with kinesin.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV000258993.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

Congenital fibrosis of the extraocular muscles (CFEOM)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 19, 2024