Submissions for variant NM_006009.4(TUBA1A):c.1265G>A (p.Arg422His)

dbSNP: rs137853050

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000007493	SCV000195272	pathogenic	Lissencephaly due to TUBA1A mutation	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000255074	SCV000321986	pathogenic	not provided	2021-10-23	criteria provided, single submitter	clinical testing	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 often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21875651, 25059107, 24860126, 22264709, 18669490, 29671837, 20466733, 26350204, 18954413, 20376468, 22948023, 18728072, 33453472, 30744660)
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000767410	SCV000898025	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 9 years old born individual of male sex. The c.1265G>A, p.(Arg422His) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Morris-Rosendahl et al. Clin Genet, 2008 PMID: 18954413. HPO-standardized clinical features were: Partial agenesis of the corpus callosum (HP:0001338); Pachygyria (HP:0001302); Cerebellar vermis hypoplasia (HP:0001320); Hypoplasia of the pons (HP:0012110); Dysgenesis of the hippocampus (HP:0025101); Dilation of lateral ventricles, Dilated fourth ventricle (HP:0006956, HP:0002198); Gray matter heterotopia (HP:0002281); Congenital microcephaly (HP:0011451); Microcephaly (HP:0000252); Muscular hypotonia (HP:0001252); Generalized tonic-clonic seizures (HP:0002069)
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	RCV000007493	SCV001451922	pathogenic	Lissencephaly due to TUBA1A mutation		criteria provided, single submitter	research	Analysis of the exome sequencing data showed a heterozygous sequence variant in TUBA1A gene. This variant is predicted as Disease Causing by MutationTaster. Sanger sequencing confirmed the variation in the proband. Parents were homozygous for the wildtype allele.
Invitae	RCV000255074	SCV002148511	pathogenic	not provided	2022-06-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg422 amino acid residue in TUBA1A. Other variant(s) that disrupt this residue have been observed in individuals with TUBA1A-related conditions (PMID: 18728072), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 7077). This missense change has been observed in individual(s) with cortical malformations (PMID: 18728072, 20466733, 26350204, 29671837). 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 422 of the TUBA1A protein (p.Arg422His).
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000007493	SCV004037187	pathogenic	Lissencephaly due to TUBA1A mutation		criteria provided, single submitter	not provided
OMIM	RCV000007493	SCV000027693	pathogenic	Lissencephaly due to TUBA1A mutation	2008-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000007493	SCV000266414	not provided	Lissencephaly due to TUBA1A mutation		no assertion provided	literature only	Classic lissencephaly
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000007493	SCV001432345	pathogenic	Lissencephaly due to TUBA1A mutation		no assertion criteria provided	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291201	SCV001479626	likely pathogenic	Lissencephaly		no assertion criteria provided	research