NM_178014.4(TUBB):c.895A>G (p.Met299Val) AND Complex cortical dysplasia with other brain malformations 6

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Mar 4, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000115018.8

Allele description [Variation Report for NM_178014.4(TUBB):c.895A>G (p.Met299Val)]

NM_178014.4(TUBB):c.895A>G (p.Met299Val)

Gene:

TUBB:tubulin beta class I [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p21.33

Genomic location:

Preferred name:

NM_178014.4(TUBB):c.895A>G (p.Met299Val)

HGVS:

NC_000006.12:g.30723957A>G
NG_034142.1:g.8757A>G
NM_001293212.2:c.955A>G
NM_001293213.2:c.370-81A>G
NM_001293214.2:c.763A>G
NM_001293215.2:c.679A>G
NM_001293216.2:c.679A>G
NM_178014.4:c.895A>GMANE SELECT
NP_001280141.1:p.Met319Val
NP_001280143.1:p.Met255Val
NP_001280144.1:p.Met227Val
NP_001280145.1:p.Met227Val
NP_821133.1:p.Met299Val
NC_000006.11:g.30691734A>G
NM_178014.2:c.895A>G
NM_178014.3:c.895A>G
NR_120608.2:n.451A>G
P07437:p.Met299Val

Protein change:

M227V; MET299VAL

Links:

UniProtKB: P07437#VAR_071763; OMIM: 191130.0001; dbSNP: rs587777355

NCBI 1000 Genomes Browser:

rs587777355

Molecular consequence:

NM_001293213.2:c.370-81A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001293212.2:c.955A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293214.2:c.763A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293215.2:c.679A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293216.2:c.679A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_178014.4:c.895A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_120608.2:n.451A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Complex cortical dysplasia with other brain malformations 6
Identifiers:: MONDO: MONDO:0014341; MedGen: C4014283; OMIM: 615771

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000148927	OMIM	no assertion criteria provided	Pathogenic (Dec 27, 2012)	germline	literature only	Breuss, M., Heng, J. I.-T., Poirier, K., Tian, G., Jaglin, X. H., Qu, Z., Braun, A., Gstrein, T., Ngo, L., Haas, M., Bahi-Buisson, N., Moutard, M. L., and 11 others Mutations in the beta-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities. Cell Rep. 2: 1554-1562, 2012.,
SCV002043789	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23246003, 25741868
SCV002579579	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004812081	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 4, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	not provided	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities.

Breuss M, Heng JI, Poirier K, Tian G, Jaglin XH, Qu Z, Braun A, Gstrein T, Ngo L, Haas M, Bahi-Buisson N, Moutard ML, Passemard S, Verloes A, Gressens P, Xie Y, Robson KJ, Rani DS, Thangaraj K, Clausen T, Chelly J, Cowan NJ, et al.

Cell Rep. 2012 Dec 27;2(6):1554-62. doi: 10.1016/j.celrep.2012.11.017. Epub 2012 Dec 13.

PubMed [citation]

PMID:: 23246003
PMCID:: PMC3595605

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000148927.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

Description

In a 2-year-old Caucasian boy with complex cortical dysplasia with other brain malformations-6 (CDCBM6; 615771), Breuss et al. (2012) identified a de novo heterozygous mutation in the TUBB gene, resulting in a met299-to-val (M299V) substitution at a highly conserved residue in a loop following helix 9. In vitro functional expression assays showed that the M299V mutation decreased the ability of the protein to assemble into tubulin heterodimers. Overexpression of the mutant protein in the developing mouse brain increased the mitotic index of neurons and decreased the number of neurons in the cortical plate, similar to findings observed in Tubb-null mice. The findings were consistent with a neuronal migratory defect. The patient had severely delayed development, microcephaly (-2.5 SD), and retinal dysplasia. Brain MRI showed focal polymicrogyria, localized band heterotopia, dysmorphic basal ganglia, partial agenesis of the corpus callosum, and hypoplastic and dysplastic cerebellum.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV002043789.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	Blood	not provided		not provided	not provided	1	not provided

From MGZ Medical Genetics Center, SCV002579579.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004812081.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Criteria applied: PS2,PS4_MOD,PS3_SUP,PM2_SUP,PP2,PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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