ClinVar Genomic variation as it relates to human health

The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30744660, 34490615, 30087272, 25131622, 25356970, 31696992, 32581362, 34402213, 33604570, 24077912, 35017693)

Based on the classification scheme VCGS_Germline_v1.3.4, 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). (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 histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 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. An alternative change to serine at the same residue has been reported as pathogenic (ClinVar). (SP). 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a recurrent pathogenic variant in patients with shared features including developmental delay, microcephaly, hypoplasia and thinning of the corpus callosum (ClinVar; LOVD; PMID: 30087272). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional and computer modelling suggest that p.(Arg2His) has subtle effects on microtubule function, possibly acting at the interdimer interface (PMID: 30087272). (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

A variant that is classified as likely pathogenic has been identified in the TUBA1A gene in a born individual of unknown sex. The c.5G>A, p.(Arg2His) variant has been reported as a variant of germline/unknown origin.

​The c.5G>A (p.R2H) alteration is located in exon 2 of the TUBA1A gene. This alteration results from a G to A substitution at nucleotide position 5. The arginine (R) at codon 2 is replaced by histidine (H).The missense change is not observed in healthy cohorts:Based on data from the NHLBI Exome Sequencing Project (ESP), the TUBA1A c.5G>A (p.R2H) alteration was not observed among 6,503 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP).The altered amino acid is conserved throughout evolution:The p.R2 amino acid is conserved throughout vertebrates.in silico prediction is conflicting:The p.R2H alteration is predicted to be benign by PolyPhen but deleterious by SIFT in silico analyses.Co-segregation analysis in our laboratory of the c.5G>A (p.R2H) alteration revealed that the unaffected mother and father did not carry this alteration, indicating a likely de novo mutation occurrence. (Note that the possibility for germline mosaicism cannot be ruled out.)Based on the available evidence, the c.5G>A (p.R2H) alteration is classified as a pathogenic mutation.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2 of the TUBA1A protein (p.Arg2His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tubulinopathy (PMID: 30087272). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 160161). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TUBA1A function (PMID: 30087272). For these reasons, this variant has been classified as Pathogenic.

The TUBA1A c.5G>A variant is predicted to result in the amino acid substitution p.Arg2His. This variant has been reported as a reoccurring de novo variant in multiple individuals with lissencephaly (see for example, Table 1, Gardner et al. 2018. PubMed ID: 30087272; Table 1, Stutterd et al. 2020. PubMed ID: 33604570; Table 1, Schröter et al. 2022. PubMed ID: 35017693). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.