rs587784491

Variant names:

• chr12-49186832-C-T
• rs587784491
• ENST00000550767.6:c.-101G>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001270400.2(TUBA1A):​c.-101G>A variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TUBA1A NM_001270400.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.9802
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 6.09

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 12-49186832-C-T is Pathogenic according to our data. Variant chr12-49186832-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 160161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49186832-C-T is described in Lovd as [Pathogenic]. Variant chr12-49186832-C-T is described in Lovd as [Likely_pathogenic]. Variant chr12-49186832-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.5G>A	p.Arg2His	missense_variant, splice_region_variant	Exon 2 of 4	ENST00000301071.12	NP_006000.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.5G>A	p.Arg2His	missense_variant, splice_region_variant	Exon 2 of 4	1	NM_006009.4	ENSP00000301071.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly due to TUBA1A mutation Pathogenic:4

-

Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with lissencephaly 3, resulting in defects in protein stability (MIM#61160; PMIDs: 20466733, 30517687). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change to serine at the same residue has been reported as pathogenic (ClinVar). (SP). 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a recurrent pathogenic variant in patients with shared features including developmental delay, microcephaly, hypoplasia and thinning of the corpus callosum (ClinVar; LOVD; PMID: 30087272). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional and computer modelling suggest that p.(Arg2His) has subtle effects on microtubule function, possibly acting at the interdimer interface (PMID: 30087272). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:2

May 15, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30744660, 34490615, 30087272, 25131622, 25356970, 31696992, 32581362, 34402213, 33604570, 24077912, 35017693) -

Mar 01, 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 histidine, which is basic and polar, at codon 2 of the TUBA1A protein (p.Arg2His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tubulinopathy (PMID: 30087272). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 160161). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TUBA1A function (PMID: 30087272). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Jul 16, 2013

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

​The c.5G>A (p.R2H) alteration is located in exon 2 of the TUBA1A gene. This alteration results from a G to A substitution at nucleotide position 5. The arginine (R) at codon 2 is replaced by histidine (H).The missense change is not observed in healthy cohorts:Based on data from the NHLBI Exome Sequencing Project (ESP), the TUBA1A c.5G>A (p.R2H) alteration was not observed among 6,503 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP).The altered amino acid is conserved throughout evolution:The p.R2 amino acid is conserved throughout vertebrates.in silico prediction is conflicting:The p.R2H alteration is predicted to be benign by PolyPhen but deleterious by SIFT in silico analyses.Co-segregation analysis in our laboratory of the c.5G>A (p.R2H) alteration revealed that the unaffected mother and father did not carry this alteration, indicating a likely de novo mutation occurrence. (Note that the possibility for germline mosaicism cannot be ruled out.)Based on the available evidence, the c.5G>A (p.R2H) alteration is classified as a pathogenic mutation. -

Neurodevelopmental disorder Pathogenic:1

Oct 27, 2020

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seizure;C0424688:Decreased head circumference;C0557874:Global developmental delay Pathogenic:1

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

TUBA1A-related disorder Pathogenic:1

Jan 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TUBA1A c.5G>A variant is predicted to result in the amino acid substitution p.Arg2His. This variant has been reported as a reoccurring de novo variant in multiple individuals with lissencephaly (see for example, Table 1, Gardner et al. 2018. PubMed ID: 30087272; Table 1, Stutterd et al. 2020. PubMed ID: 33604570; Table 1, Schröter et al. 2022. PubMed ID: 35017693). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Tubulinopathy-associated dysgyria Pathogenic:1

Nov 01, 2021

Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Tubulinopathy Pathogenic:1

Jul 01, 2018

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

A variant that is classified as likely pathogenic has been identified in the TUBA1A gene in a born individual of unknown sex. The c.5G>A, p.(Arg2His) variant has been reported as a variant of germline/unknown origin. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.50	T;D;T
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Pathogenic	3.1	M;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.1	N;N;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0090	D;D;T
Sift4G	Benign	0.081	T;T;T
Polyphen		0.81	P;P;.
Vest4		0.42
MutPred		0.58		Gain of catalytic residue at S6 (P = 9e-04);Gain of catalytic residue at S6 (P = 9e-04);Gain of catalytic residue at S6 (P = 9e-04);
MVP		0.87
MPC		4.2
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.43
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.79
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: rs587784491; hg19: chr12-49580615;