ClinVar Miner

Submissions for variant NM_006009.4(TUBA1A):c.1204C>T (p.Arg402Cys) (rs587784483)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV000663417 SCV000786716 pathogenic Limb-girdle muscular dystrophy, type 2D criteria provided, single submitter research The heterozygous p.Arg402Cysvariant was identified by our study in one individual with Lissencephaly. The p.Arg402Cys variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases.
GeneDx RCV000494633 SCV000582635 pathogenic not provided 2017-05-15 criteria provided, single submitter clinical testing The R402C variant in the TUBA1A gene is a recurrent pathogenic variant that has been previously reported as a de novo variant in individuals with lissencephaly (Poirier et al., 2007; Morris-Rosendahl et al., 2008; Kumar et al., 2010). Functional studies demonstrate a reduced yield and compromised stability of tubulin heterodimers; however, studies are conflicting regarding their ability to successfully assemble into microtubules (Tian et al., 2010; Yokoi et al., 2015). The R402C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R402C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Furthermore, missense variants at the same residue (R402L/H) and in a nearby residue (L397P) have been reported in the Human Gene Mutation Database in association with TUBA1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the presence of R402C is consistent with a diagnosis of a TUBA1A-related disorder in this individual.
GeneReviews RCV000147798 SCV000266412 pathogenic Lissencephaly 3 2015-12-04 no assertion criteria provided literature only Classic lissencephaly
Genetic Services Laboratory, University of Chicago RCV000147798 SCV000195269 pathogenic Lissencephaly 3 2013-11-05 criteria provided, single submitter clinical testing
Institute of Human Genetics,Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000767408 SCV000898023 pathogenic Tubulinopathies 2018-07-01 criteria provided, single submitter literature only A variant that is classified as pathogenic has been identified in the TUBA1A gene in a 11 years old born individual of female sex. The c.1204C>T, p.(Arg402Cys) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Morris-Rosendahl et al. Clin Genet, 2008 PMID: 18954413. HPO-standardized clinical features were: Partial agenesis of the corpus callosum, Hypoplasia of the corpus callosum (HP:0001338, HP:0002079); Agyria (HP:0031882); Cerebellar vermis hypoplasia (HP:0001320); Hypoplasia of the pons (HP:0012110); no Abnormal morphology of the hippocampus (HP:0025100); Dilation of lateral ventricles (HP:0006956); Congenital microcephaly (HP:0011451); Microcephaly (HP:0000252); Spasticity, muscular hypotonia (HP:0001257, HP:0001252); Generalized tonic-clonic seizures (HP:0002069); Strabismus, Nystagmus (HP:0000486, HP:0000639)

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