chr12-49185162-G-A

Position:

• chr12-49185162-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_006009.4(TUBA1A):​c.1204C>T​(p.Arg402Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R402H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 1.31

Genes affected

TUBA1A (HGNC:20766): (tubulin alpha 1a) Microtubules of the eukaryotic cytoskeleton perform essential and diverse functions and are composed of a heterodimer of alpha and beta tubulins. The genes encoding these microtubule constituents belong to the tubulin superfamily, which is composed of six distinct families. Genes from the alpha, beta and gamma tubulin families are found in all eukaryotes. The alpha and beta tubulins represent the major components of microtubules, while gamma tubulin plays a critical role in the nucleation of microtubule assembly. There are multiple alpha and beta tubulin genes, which are highly conserved among species. This gene encodes alpha tubulin and is highly similar to the mouse and rat Tuba1 genes. Northern blot studies have shown that the gene expression is predominantly found in morphologically differentiated neurologic cells. This gene is one of three alpha-tubulin genes in a cluster on chromosome 12q. Mutations in this gene cause lissencephaly type 3 (LIS3) - a neurological condition characterized by microcephaly, intellectual disability, and early-onset epilepsy caused by defective neuronal migration. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

TUBA1B-AS1 (HGNC:56356): (TUBA1B antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_006009.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49185161-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBA1A. . Gene score misZ 5.584 (greater than the threshold 3.09). Trascript score misZ 8.7455 (greater than threshold 3.09). GenCC has associacion of gene with tubulinopathy-associated dysgyria, intellectual disability, autosomal dominant 40, tubulinopathy, lissencephaly due to TUBA1A mutation.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 12-49185162-G-A is Pathogenic according to our data. Variant chr12-49185162-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 160146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185162-G-A is described in Lovd as [Pathogenic]. Variant chr12-49185162-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.1204C>T	p.Arg402Cys	missense_variant	4/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.1204C>T	p.Arg402Cys	missense_variant	4/4
TUBA1A	NM_001270400.2	c.1099C>T	p.Arg367Cys	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.1204C>T	p.Arg402Cys	missense_variant	4/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-3121G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly due to TUBA1A mutation Pathogenic:5 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Missense variant c.1204C>T in Exon 4 of the TUBA1A gene that results in the amino acid substitution p.Arg402Cys was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 160146]. The observed variation has previosuly been reported for tubulinopathy by Hebebrand, Moritz, et al., 2019. For these reasons this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 05, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics, Suma Genomics	-	- -
not provided, no classification provided	literature only	GeneReviews	-	Classic lissencephaly -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Apr 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 12, 2022	This variant has been reported in the literature in at least 8 individuals with lissencephaly, and as de novo in at least 5 of these individuals (Selected publications: Poirier 2007 PMID:17584854; Morris-Rosendahl 2008 PMID:18954413; Kumar 2010 PMID:20466733; Di Donato 2018 PMID:29671837). This variant is absent from large control databases but is present in ClinVar, with several laboratories classifying it as pathogenic (Variation ID:160146). In vitro functional studies have shown a deleterious effect of this variant on the protein, including causing a defect in the tubulin heterodimer assembly pathway (Tian 2010 PMID:20603323; Aiken 2019 PMID:30517687). An in vivo functional study in a mouse model suggests that this variant results in defective neuronal migration (Aiken 2019 PMID:30517687). Evolutionary conservation and computational predictive tools support a deleterious effect of this variant on the protein. Of note, this amino acid position, p.Arg402, is the most common location for pathogenic variants in the TUBA1A gene, further supporting the functional importance of this residue (Hebebrand 2019 PMID:30744660; Aiken 2019 PMID:30517687). In summary, this variant is classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 02, 2021	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects TUBA1A protein function (PMID: 30517687). This variant has been observed in individual(s) with TUBA1A-related cortical malformations (PMID: 20466733, 17584854). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 160146). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 402 of the TUBA1A protein (p.Arg402Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2022	Published functional studies demonstrate reduced yield, compromised stability of tubulin heterodimers, and decreased cortical neuron migration (Tian et al., 2010; Aiken et al., 2019); however, studies are conflicting regarding their ability to successfully assemble into microtubules (Yokoi et al., 2015); Not observed at significant frequency 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: 25059107, 20603323, 22264709, 26493046, 17584854, 18954413, 20466733, 21292473, 30517687, 29671837, 30744660, 24860126) -

Lissencephaly Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

Autosomal recessive limb-girdle muscular dystrophy type 2D Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous p.Arg402Cysvariant was identified by our study in one individual with Lissencephaly. The p.Arg402Cys variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases. -

Tubulinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

literature only

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Jul 01, 2018

A variant that is classified as pathogenic has been identified in the TUBA1A gene in a 11 years old born individual of female sex. The c.1204C>T, p.(Arg402Cys) 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, Hypoplasia of the corpus callosum (HP:0001338, HP:0002079); Agyria (HP:0031882); Cerebellar vermis hypoplasia (HP:0001320); Hypoplasia of the pons (HP:0012110); no Abnormal morphology of the hippocampus (HP:0025100); Dilation of lateral ventricles (HP:0006956); Congenital microcephaly (HP:0011451); Microcephaly (HP:0000252); Spasticity, muscular hypotonia (HP:0001257, HP:0001252); Generalized tonic-clonic seizures (HP:0002069); Strabismus, Nystagmus (HP:0000486, HP:0000639) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.051	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.89
MutPred		0.88		Gain of catalytic residue at A403 (P = 0.0014);Gain of catalytic residue at A403 (P = 0.0014);.;
MVP		0.97
MPC		4.3
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.81
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587784483; hg19: chr12-49578945;