ClinVar Miner

Submissions for variant NM_006009.4(TUBA1A):c.518C>T (p.Pro173Leu)

dbSNP: rs1565627304
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000767490 SCV000898105 pathogenic Tubulinopathy 2018-07-01 criteria provided, single submitter clinical testing A variant that is classified as pathogenic has been identified in the TUBA1A gene in a born individual of male sex. The c.518C>T, p.(Pro173Leu) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Hebebrand et al. Orphanet J. Rare. Dis., 2019 PMID: 30744660. HPO-standardized clinical features were: Hypoplasia of the corpus callosum (HP:0002079); Cerebellar vermis hypoplasia (HP:0001320); Hypoplastic hippocampus (HP:0025517); Dilation of lateral ventricles (HP:0006956); Microcephaly (HP:0000252); Spasticity, muscular hypotonia (HP:0001257, HP:0001252); Focal seizures (HP:0007359); Strabismus (HP:0000486)
Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg RCV001803973 SCV002047679 pathogenic Tubulinopathy-associated dysgyria 2021-11-01 criteria provided, single submitter research
GeneDx RCV001528974 SCV002499022 pathogenic not provided 2022-03-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28714951, 25363768, 22495306, 28407358, 30744660, 34011629, 33726816, 31785789, 35017693, 24860126)
MGZ Medical Genetics Center RCV002290011 SCV002580279 pathogenic Lissencephaly due to TUBA1A mutation 2022-03-23 criteria provided, single submitter clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV002290011 SCV002820204 likely pathogenic Lissencephaly due to TUBA1A mutation criteria provided, single submitter clinical testing The missense variant p.P173L in TUBA1A (NM_006009.4) has been previously reported in an individual affected with TUBA1A-associated tubulinopathy (Hebebrand et al, 2019). The p.P173L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and leucine. The p.P173L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 173 of TUBA1A is conserved in all mammalian species. The nucleotide c.518 in TUBA1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Invitae RCV001528974 SCV003441259 uncertain significance not provided 2022-09-27 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). 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. 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 expected to disrupt TUBA1A protein function. ClinVar contains an entry for this variant (Variation ID: 625511). This missense change has been observed in individual(s) with tubulinopathy (PMID: 24860126). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 173 of the TUBA1A protein (p.Pro173Leu).
Ambry Genetics RCV002536596 SCV003706329 pathogenic Inborn genetic diseases 2021-11-09 criteria provided, single submitter clinical testing The c.518C>T (p.P173L) alteration is located in exon 4 (coding exon 4) of the TUBA1A gene. This alteration results from a C to T substitution at nucleotide position 518, causing the proline (P) at amino acid position 173 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported de novo in multiple unrelated patients with global developmental delay, cortical and subcortical malformations, microcephaly, spasticity, and epilepsy (Bahi-Buisson, 2014; Hebebrand, 2019; DECIPHER). 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). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001528974 SCV001741646 likely pathogenic not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001528974 SCV001797905 likely pathogenic not provided no assertion criteria provided clinical testing

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