ClinVar Genomic variation as it relates to human health

This variant has been reported in the literature in at least 8 individuals with lissencephaly, and as de novo in at least 5 of these individuals (Selected publications: Poirier 2007 PMID:17584854; Morris-Rosendahl 2008 PMID:18954413; Kumar 2010 PMID:20466733; Di Donato 2018 PMID:29671837). This variant is absent from large control databases but is present in ClinVar, with several laboratories classifying it as pathogenic (Variation ID:160146). In vitro functional studies have shown a deleterious effect of this variant on the protein, including causing a defect in the tubulin heterodimer assembly pathway (Tian 2010 PMID:20603323; Aiken 2019 PMID:30517687). An in vivo functional study in a mouse model suggests that this variant results in defective neuronal migration (Aiken 2019 PMID:30517687). Evolutionary conservation and computational predictive tools support a deleterious effect of this variant on the protein. Of note, this amino acid position, p.Arg402, is the most common location for pathogenic variants in the TUBA1A gene, further supporting the functional importance of this residue (Hebebrand 2019 PMID:30744660; Aiken 2019 PMID:30517687). In summary, this variant is classified as pathogenic.

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.

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)

Published functional studies demonstrate reduced yield, compromised stability of tubulin heterodimers, and decreased cortical neuron migration (Tian et al., 2010; Aiken et al., 2019); however, studies are conflicting regarding their ability to successfully assemble into microtubules (Yokoi et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 25059107, 20603323, 22264709, 26493046, 17584854, 18954413, 20466733, 21292473, 30517687, 29671837, 30744660, 24860126)

A Heterozygous Missense variant c.1204C>T in Exon 4 of the TUBA1A gene that results in the amino acid substitution p.Arg402Cys was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 160146]. The observed variation has previosuly been reported for tubulinopathy by Hebebrand, Moritz, et al., 2019. For these reasons this variant has been classified as Likely Pathogenic.

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects TUBA1A protein function (PMID: 30517687). This variant has been observed in individual(s) with TUBA1A-related cortical malformations (PMID: 20466733, 17584854). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 160146). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 402 of the TUBA1A protein (p.Arg402Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine.

Classic lissencephaly