ClinVar Miner

Submissions for variant NM_006009.4(TUBA1A):c.641G>A (p.Arg214His) (rs1057517843)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000413283 SCV000511367 pathogenic not provided 2017-02-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000496159 SCV000893302 pathogenic Lissencephaly 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000413283 SCV000490865 pathogenic not provided 2018-10-05 criteria provided, single submitter clinical testing The R214H variant in the TUBA1A gene has been reported previously as a de novo heterozygous pathogenic variant in an individual with severe developmental delay, nearly absent speech, seizures, microcephaly, roving eye movements and brain MRI findings of hypoplastic vermis, asymmetrical pons, diffuse irregular gyration and sulcation of the cortex, partial agenesis of the corpus callosum, mild ventriculomegaly, basal ganglia dysplasia, globular thalami, moderate cranial nerve hypoplasia, deficient falx, and bilateral colobomas (Oegema et al., 2015). A fetus identified by prenatal ultrasonography and MRI with unlayered central and asymmetric polymicrogyria, agenesis of the corpus callosum, mild vermian hypoplasia, mild dysplastic olivary nuclei, heterotopia, and unilateral olfactory bulb agenesis, was also found to harbor the de novo heterozygous R214H variant (Bahi-Buisson et al., 2014; Fallet-Bianco et al., 2014). The R214H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R214H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs within the intermediate domain at a position that is conserved across species. Functional studies of the R214H mutant protein expressed in HEK93 cells demonstrated diminished microtubule reintegration, as compared to the wild type protein, following cold-induced depolymerization (Oegema et al., 2015). Additionally, missense variants at the same residue (R214L) and in nearby residues (Y210C; D218Y/N; I219V) have been reported at GeneDx and 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 R214His consistent with the diagnosis of a TUBA1A-related disorder in this individual.
Institute of Human Genetics,Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000496159 SCV000586724 pathogenic Lissencephaly 3 2017-08-01 criteria provided, single submitter clinical testing De novo missense variant identified in a female patient with severe ID, severe epilepsy, developmental regression, scoliosis, hypotonia, MRI: agenesis of corpus callosum, Dandy-Walker malformation, opticus hypoplasia, delayed bone age.
Institute of Human Genetics,Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000767423 SCV000898038 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 51 months old born individual of female sex. The c.641G>A, p.(Arg214His) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Oegema et al. Hum Mol Genet, 2015 PMID: 26130693. HPO-standardized clinical features were: Partial agenesis of the corpus callosum (HP:0001338); Other (NA); Cerebellar vermis hypoplasia (HP:0001320); no Abnormal morphology of the hippocampus (HP:0025100); Dilation of lateral ventricles (HP:0006956); Microcephaly (HP:0000252); Generalized tonic-clonic seizures (HP:0002069)

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