Submissions for variant NM_006009.4(TUBA1A):c.367C>T (p.Arg123Cys)

dbSNP: rs886039513

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256088	SCV000322208	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing	In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24860126, 26934450, 29325622, 26003063, 25666757, 28677066, 29057214, 32989326, 30744660, 27535533, 24077912)
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000767482	SCV000898097	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 3 years old born individual of female sex. The c.367C>T, p.(Arg123Cys) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Bahi-Buisson et al. Brain, 2014 PMID: 24860126. HPO-standardized clinical features were: no Abnormal corpus callosum morphology (-HP:0001273); Polymicrogyria (HP:0002126); Dysgenesis of the cerebellar vermis (HP:0002195); Microcephaly (HP:0000252)
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV002229725	SCV002507299	likely pathogenic	Lissencephaly due to TUBA1A mutation	2021-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003352816	SCV004076633	pathogenic	Inborn genetic diseases	2023-07-05	criteria provided, single submitter	clinical testing	The c.367C>T (p.R123C) alteration is located in exon 3 (coding exon 3) of the TUBA1A gene. This alteration results from a C to T substitution at nucleotide position 367, causing the arginine (R) at amino acid position 123 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in two individuals with features consistent with TUBA1A-related lissencephaly (McMichael, 2015; Bahi-Buisson, 2014). Another alteration at the same codon, c.368G>A (p.R123H), has been described in a 52 year old male with hypoplasia of the corpus callosum, brainstem dysplasia, abnormality of the internal capsule, congenital microcephaly and infantile spasms. This variant was reported to be de novo (Hebebrand, 2019). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000256088	SCV004295047	pathogenic	not provided	2023-03-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TUBA1A protein function. ClinVar contains an entry for this variant (Variation ID: 265378). This missense change has been observed in individual(s) with cortical malformations (PMID: 24860126, 25666757). 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 cysteine, which is neutral and slightly polar, at codon 123 of the TUBA1A protein (p.Arg123Cys).
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002229725	SCV005440644	likely pathogenic	Lissencephaly due to TUBA1A mutation		criteria provided, single submitter	clinical testing	PM2_Supporting+PS2_Moderate+PP3_Moderate+PP2+PS4_Supporting
Yale Center for Mendelian Genomics, Yale University	RCV001849353	SCV002106907	uncertain significance	Cerebral palsy	2020-09-28	no assertion criteria provided	literature only