12-49185102-G-A

Variant names:

• chr12-49185102-G-A
• rs137853049
• NM_006009.4:c.1264C>T

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.1264C>T​(p.Arg422Cys) variant causes a missense change. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R422H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.84

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 helix (size 17) in uniprot entity TBA1A_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 chr12-49185101-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in the TUBA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 163 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 5.584 (above the threshold of 3.09). Trascript score misZ: 8.7455 (above the threshold of 3.09). GenCC associations: The gene is linked to tubulinopathy-associated dysgyria, intellectual disability, autosomal dominant 40, tubulinopathy, lissencephaly due to TUBA1A mutation.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 12-49185102-G-A is Pathogenic according to our data. Variant chr12-49185102-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185102-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.1264C>T	p.Arg422Cys	missense_variant	Exon 4 of 4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.1264C>T	p.Arg422Cys	missense_variant	Exon 4 of 4		NP_001257328.1
TUBA1A	NM_001270400.2	c.1159C>T	p.Arg387Cys	missense_variant	Exon 4 of 4		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.1264C>T	p.Arg422Cys	missense_variant	Exon 4 of 4	1	NM_006009.4	ENSP00000301071.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly due to TUBA1A mutation Pathogenic:2

Oct 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classification according to ACMG guidelines of c.1264C>T:p.(Arg422Cys) in TUBA1A: pathogenic. - PS2: new mutation (further independent validation is pending). - PM1: the variant is located in a mutation hotspot and/or a critical and well established functional domain - PM2: The variant has not been identified in any population genetic studies (such as GnomAD, Iranome, GME, 1kGP, etc.) identified. - PP2: sense-changing variant in a gene that has a low rate of benign sense-changing variants and in which sense-changing variants are a common disease mechanism. are. - PP3: Bioinformatics prediction programs classify this variant as pathogenic. The gene TUBA1A codes for tubulin alpha 1a, which is particularly expressed in the brain. The TUBA1A-associated tubulinopathy (lissencephaly) is an autosomal dominant and clinically very in which brain malformations, microcephaly, developmental delay, and epilepsy are the main clinical and epilepsy, mainly caused by new mutations in TUBA1A. The new mutation c.1264C>T:p.(Arg422Cys) has been described several times in patients with lissencephaly. -

not provided Pathogenic:2

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 422 of the TUBA1A protein (p.Arg422Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cortical malformations (PMID: 18728072). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7076). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TUBA1A protein function with a positive predictive value of 80%. This variant disrupts the p.Arg422 amino acid residue in TUBA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18728072, 20466733, 26350204, 29671837). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dec 19, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; This variant is associated with the following publications: (PMID: 20466733, 18728072, 20376468, 22264709, 28412269, 24860126, 30744660, 33064843, 36028527, 24077912, 27535533) -

Inborn genetic diseases Pathogenic:1

Dec 04, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tubulinopathy Pathogenic:1

Jul 01, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

A variant that is classified as pathogenic has been identified in the TUBA1A gene in a 54 months old born individual of female sex. The c.1264C>T, p.(Arg422Cys) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Bahi-Buisson et al. J Med Genet, 2008 PMID: 18728072. HPO-standardized clinical features were: Hypoplasia of the corpus callosum (HP:0002079); Pachygyria (HP:0001302); Cerebellar vermis hypoplasia (HP:0001320); Abnormality of the internal capsule (HP:0012502); Microcephaly (HP:0000252); Spasticity (HP:0001257); no Seizures (-HP:0001250) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	2.9	M;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.
Sift4G	Benign	0.088	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.84
MutPred		0.85		Loss of disorder (P = 0.111);Loss of disorder (P = 0.111);.;
MVP		0.96
MPC		4.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.78
gMVP		0.98

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: rs137853049; hg19: chr12-49578885; COSMIC: COSV55497560; COSMIC: COSV55497560;