ClinVar Miner

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

dbSNP: rs886039513
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Total submissions: 7
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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

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