ClinVar Miner

Submissions for variant NM_006009.4(TUBA1A):c.5G>A (p.Arg2His) (rs587784491)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000147815 SCV000195288 likely pathogenic Lissencephaly 3 2013-10-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000190671 SCV000244111 pathogenic Inborn genetic diseases 2013-07-16 criteria provided, single submitter clinical testing ​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.
GeneDx RCV000494655 SCV000582422 likely pathogenic not provided 2015-10-03 criteria provided, single submitter clinical testing The R2H variant in the TUBA1A gene has been published as a de novo variant in an individual reported with a clinical diagnosis of lissencephaly 3 (Farwell et al., 2015). The R2H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R2H variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The R2H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Institute of Human Genetics,Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000767455 SCV000898070 likely pathogenic Tubulinopathies 2018-07-01 criteria provided, single submitter literature only 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.
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire,Universite Libre de Bruxelles RCV000147815 SCV000998515 pathogenic Lissencephaly 3 criteria provided, single submitter clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes RCV001375034 SCV001572322 pathogenic Neurodevelopmental disorder 2020-10-27 criteria provided, single submitter clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000147815 SCV001133166 pathogenic Lissencephaly 3 2019-09-26 no assertion criteria provided clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003601 SCV001161995 likely pathogenic Global developmental delay; Seizures; Decreased head circumference no assertion criteria provided research

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