ClinVar Genomic variation as it relates to human health

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.

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)

The heterozygous p.Arg214His variant in TUBA1A was identified by our study in one individual with lissencephaly. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies. 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 TUBA1A gene has a low rate of benign missense variation, supporting that a change in this position may not be tolerated. This variant has been reported in ClinVar (Variation ID: 372542). Multiple reports of de novo inheritance of this variant were reported in ClinVar and the literature. In summary, the p.Arg214His variant is pathogenic based off of our findings, multiple de novo reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PS2, PM6_Strong, PP2 (Richards 2015).

This variant was classified as: Likely pathogenic.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372542). Different missense changes at the same codon (p.Arg214Cys, p.Arg214Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000432708, VCV001187068). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

ACMG classification criteria: PS4 strong, PM2 moderated, PM6 moderated, PP2 supporting, PP3 supporting

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TUBA1A function (PMID: 26130693). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). ClinVar contains an entry for this variant (Variation ID: 372542). This missense change has been observed in individual(s) with lissencephaly, including several cases in which the variant was observed to be de novo (PMID: 24860126, 26130693, 29158550; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 214 of the TUBA1A protein (p.Arg214His).

The c.641G>A (p.R214H) alteration is located in exon 4 (coding exon 4) of the TUBA1A gene. This alteration results from a G to A substitution at nucleotide position 641, causing the arginine (R) at amino acid position 214 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the TUBA1A c.641G>A alteration was not observed, with coverage at this position. This alteration was reported de novo in multiple patients with developmental delay and abnormal brain MRI findings (Bahi-Buisson, 2014; Oegema, 2015; Hedebrand, 2019). The p.R214 amino acid is conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional analysis in HEK93 cells following cold-induced depolymerization, demonstrated that the p.R214H alteration showed reduced microtubule reintegration compared to wildtype, suggesting that the arginine-to-histidine substitution subtly perturbs the rate that affected heterodimers integrate into growing microtubules (Oegema, 2015). The in silico prediction for the p.R214H alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

Not observed 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 a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 29158550, 26130693, 26934450, 25059107, 24860126, 28677066, 30744660, 30087272, 32570172)