NM_001069.2(TUBB2A):c.743C>T (p.Ala248Val) AND Cortical dysplasia, complex, with other brain malformations 5

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Jan 1, 2018
Review status:: criteria provided, conflicting classifications

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:: RCV000114959.2

Allele description

NM_001069.2(TUBB2A):c.743C>T (p.Ala248Val)

Gene:

TUBB2A:tubulin beta 2A class IIa [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p25.2

Genomic location:

Preferred name:

NM_001069.2(TUBB2A):c.743C>T (p.Ala248Val)

HGVS:

NC_000006.12:g.3154458G>A
NG_042223.1:g.8092C>T
NM_001069.2:c.743C>T
NP_001060.1:p.Ala248Val
NC_000006.11:g.3154692G>A
Q13885:p.Ala248Val

Protein change:

A248V; ALA248VAL

Links:

UniProtKB: Q13885#VAR_071169; OMIM: 615101.0002; dbSNP: rs2808001

NCBI 1000 Genomes Browser:

rs2808001

Molecular consequence:

NM_001069.2:c.743C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cortical dysplasia, complex, with other brain malformations 5 (CDCBM5)
Identifiers:: MedGen: C3810407; OMIM: 615763

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000148869	OMIM	no assertion criteria provided	Pathogenic (Apr 3, 2014)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000693794	NeuroMeGen,Hospital Clinico Santiago de Compostela	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2018)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000148869

OMIM

no assertion criteria provided

Pathogenic
(Apr 3, 2014)

germline

literature only

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

SCV000693794

NeuroMeGen,Hospital Clinico Santiago de Compostela

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 1, 2018)

de novo

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	de novo	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy.

Cushion TD, Paciorkowski AR, Pilz DT, Mullins JG, Seltzer LE, Marion RW, Tuttle E, Ghoneim D, Christian SL, Chung SK, Rees MI, Dobyns WB.

Am J Hum Genet. 2014 Apr 3;94(4):634-41. doi: 10.1016/j.ajhg.2014.03.009.

PubMed [citation]

PMID:: 24702957
PMCID:: PMC3980418

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, SCV000148869.1

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

Description

In a girl with complex cortical dysplasia with other brain malformations-5 (CDCBM5; 615763), Cushion et al. (2014) identified a de novo heterozygous c.743C-T transition in the TUBB2A gene, resulting in an ala248-to-val (A248V) substitution at a highly conserved residue in a loop at the intradimer interface that is a critical GTP-binding site for microtubule polymerization. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes, or Exome Variant Server databases. The A248V mutant protein decreased incorporation into the in vitro cytoskeleton network compared to wildtype, with more of the mutant protein remaining unpolymerized in the cytoplasm. These findings correlated with the less severe brain malformations seen in this child compared to those in a child with a different TUBB2A mutation (N247K; 615101.0001).

#	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 NeuroMeGen,Hospital Clinico Santiago de Compostela, SCV000693794.1

#	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	de novo	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Mar 11, 2018

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