ClinVar Miner

Submissions for variant NM_006009.4(TUBA1A):c.1168C>T (p.Arg390Cys) (rs1064793286)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483973 SCV000565643 pathogenic not provided 2017-02-15 criteria provided, single submitter clinical testing The R390C pathogenic variant in the TUBA1A gene has been reported previously in an individual with complete agenesis of the corpus callosum, moderate cerebellar hypoplasia, and a simplified gyral pattern similar to a mild lissencephaly (Kumar et al., 2010). The same variant was also identified in an individual with microcephaly, severe hypotonia, strabismus, polymicrogyria with dysmorphic basal ganglia, a dysplastic cerebellar vermis, severe hypoplasia of the brainstem, and corpus callosal hypoplasia (Poirier et al., 2013) as well as in another individual with polymicrogyria-like corical dysplasia (Bahi-Buisson et al., 2014). The R390C pathogenic variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R390C 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 moderately conserved across species; the c.1168 C>T change is seen in some mammals. In silico analysis is inconsistent in its predictions as to whether or not the mutation is damaging to the protein structure/function. Missense variants at the same and nearby residues (R390H, A387V, D396Y, L397P) have been reported in the Human Gene Mutation Database in association with tubulinopathy-associated brain malformations (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R390C as a pathogenic variant.
Institute of Human Genetics,Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000767411 SCV000898026 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 born individual of unknown sex. The c.1168C>T, p.(Arg390Cys) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Kumar et al. Hum Mol Genet, 2010 PMID: 20466733. HPO-standardized clinical features were: Agenesis of the corpus callosum (HP:0001274); Cortical gyral simplification (HP:0009879); Cerebellar hypoplasia (HP:0001321)

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