Submissions for variant NM_006009.4(TUBA1A):c.1169G>C (p.Arg390Pro)

dbSNP: rs1064796460

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486649	SCV000573195	pathogenic	not provided	2017-11-21	criteria provided, single submitter	clinical testing	The R390P variant in the TUBA1A gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, different missense variants at the same position (R390C, R390H) have been reported as de novo variants in individuals with TUBA1A-related disorders (Kumar et al., 2010; Poirier et al., 2013; Zanni et al., 2013). The R390P variant is not observed in large population cohorts (Lek et al., 2016). The R390P 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. In-silico analyses, including protein predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. Targeted parental testing results indicate this variant was apparently de novo in a patient tested at GeneDx.
Department of Pediatrics, Driscoll Children's Hospital	RCV000770768	SCV000852008	pathogenic	Lissencephaly due to TUBA1A mutation		criteria provided, single submitter	clinical testing	The Arg390Pro mutation in TUBA1A gene reported in our study is associated with a broader clinical phenotype than previously reported. The cerebral dysgenesis includes severe lissencephaly, polymicrogyria, and agenesis of both the corpus callosum and cerebellum. The extra-cranial manifestations of cleft palate and optic nerve hypoplasia have not been previously reported. This single amino acid substitution of a positively charged arginine with a neutrally-charged proline strongly suggests a change in the protein configuration and function of tubulin which resulted in altered function of microtubules that are crucial in normal neuronal migration and cerebral development.
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000767439	SCV000898054	likely pathogenic	Tubulinopathy	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.1169G>C, p.(Arg390Pro) variant has been reported as a variant of germline/unknown origin.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000770768	SCV000924565	likely pathogenic	Lissencephaly due to TUBA1A mutation	2018-06-15	criteria provided, single submitter	research	The heterozygous p.Arg390Pro variant was identified by our study in one individual with lissencephaly. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, supporting that a change at this position may not be tolerated. Other variants at this position, all de novo, have been reported pathogenic in the literature, supporting the likelihood that this is a pathogenic variant (Poirier et al. 2013, PMID: 20466733; Kumar et al. 2010, PMID: 22948023; Zanni et al. 2013, PMID: 23317684). In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic.