Submissions for variant NM_006009.4(TUBA1A):c.449C>T (p.Thr150Ile)

dbSNP: rs1565627339

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000767488	SCV000898103	pathogenic	Tubulinopathy	2018-07-01	criteria provided, single submitter	literature only	A variant that is classified as pathogenic has been identified in the TUBA1A gene in a 20 months old born individual of female sex. The c.449C>T, p.(Thr150Ile) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Romaniello et al. Eur Radiol, 2017 PMID: 28677066. HPO-standardized clinical features were: Hypoplasia of the corpus callosum (HP:0002079); Perisylvian polymicrogyria (HP:0012650); Cerebellar vermis hypoplasia (HP:0001320); Brainstem dysplasia (HP:0002508); Dilated fourth ventricle (HP:0002198); Abnormality of the internal capsule (HP:0012502); Congenital microcephaly (HP:0011451); Muscular hypotonia (HP:0001252); no Seizures (-HP:0001250); Strabismus, Nystagmus (HP:0000486, HP:0000639)
GeneDx	RCV001550367	SCV001770682	pathogenic	not provided	2019-06-29	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30744660, 28677066)
Invitae	RCV001550367	SCV002222004	uncertain significance	not provided	2021-01-30	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of tubulin-related cortical malformations (PMID: 28677066). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 625509). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 150 of the TUBA1A protein (p.Thr150Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470974	SCV002768426	likely pathogenic	Lissencephaly due to TUBA1A mutation	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine (exon 4). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions. (N) 0600 - Variant is located in an annotated domain or motif (tubulin domain; PDB). (N) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a de novo mutation in an identical twin-pair with cerebellar dysplasia (PMID:28677066; ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign