ClinVar Genomic variation as it relates to human health

The R64W variant in the TUBA1A gene has been reported previously as a de novo change in an individual with thin cerebral parenchyma, agenesis of the cerebellum and corpus callosum, hypoplastic brain stem, focal seizures, and spastic tetraplegia (Yokoi et al., 2015). Functional studies suggest that R64W impairs microtubule stability (Yokoi et al., 2015). The R64W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R64W 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function.

A variant that is classified as pathogenic has been identified in the TUBA1A gene in a 3 years old born individual of female sex. The c.190C>T, p.(Arg64Trp) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Yokoi et al. Sci Rep, 2015 PMID: 26493046. HPO-standardized clinical features were: Agenesis of the corpus callosum (HP:0001274); Other (NA); Hypoplasia of the brainstem (HP:0002365); Cerebellar agenesis (HP:0012642); Dilation of lateral ventricles (HP:0006956); Congenital microcephaly (HP:0011451); Spasticity, muscular hypotonia (HP:0001257, HP:0001252); Focal seizures (HP:0007359); Optic nerve hypoplasia (HP:0000609)

The heterozygous p.Arg64Trp variant in TUBA1A was identified by our study in a family with lissencephaly 3. Trio exome analysis showed this variant to be de novo. The variant has also been reported de novo in one individual with confirmed paternity and maternity, and inherited from an unaffected father who was mosaic in another proband with lissencephaly (PMIDs: 26493046, 36658419). It was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 420581) and has been interpreted as pathogenic by GeneDx and Institute of Human Genetics, FAU Erlangen. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in TUBB2B in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant lissencephaly 3. ACMG/AMP Criteria applied: PS2_Moderate, PM2_Supporting, PP3_Moderate, PP2 (Richards 2015).

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with lissencephaly 3, resulting in defects in protein stability (MIM#61160; PMIDs: 20466733, 30517687). A phenotypic spectrum including congenital fibrosis of the extraocular muscles has also been described (PMID: 33649541). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4; 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg64Gln) has been reported as likely pathogenic by a clinical laboratory (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has previously been observed in multiple unrelated, affected individuals including two de novo occurrences (PMIDs: 26493046, 36658419, 36403095, 32149430). In addition, it has also been reported as pathogenic by a clinical laboratory (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign