rs587784491

chr12-49186832-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_006009.4(TUBA1A):c.5G>A(p.Arg2His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/2 splice prediction tools predicting alterations to normal splicing. 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. R2S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TUBA1A NM_006009.4 missense, splice_region
• 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49186833-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 625482.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, TUBA1A
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• 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/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.5G>A	p.Arg2His	missense_variant, splice_region_variant	2/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.5G>A	p.Arg2His	missense_variant, splice_region_variant	2/4
TUBA1A	NM_001270400.2	c.-101G>A		splice_region_variant, 5_prime_UTR_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.5G>A	p.Arg2His	missense_variant, splice_region_variant	2/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-1451C>T		intron_variant, non_coding_transcript_variant

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 09, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. Haploinsufficiency has been suggested as a mechanism caused also by missense variants. (PMID: 30517687). (N) 0104 - Dominant Negative is a mechanism of disease for this gene. Missense variants have been reported to have a dominant-negative effect, which is speculated to be the prevalent mechanism of TUBA1A (PMID: 30517687). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and high conservation. (N) 0600 - Variant is located in an annotated domain or motif (tubulin alpha chain PTZ00335 domain; NCBI). (N) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region) (Decipher). (P) 0704 - Comparable variant has low previous evidence for pathogenicity. At least one patient with an alternative change in the same residue resulting in a serine has been reported pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported pathogenic in multiple patients (ClinVar; LOVD; PMID: 30087272). (P) 0905 - No segregation evidence has been identified for this variant, in the literature. (N) 1002 - 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). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2013

​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

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 27, 2020

- -

TUBA1A-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2024

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. -

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

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Tubulinopathy Pathogenic:1

Likely 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 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. -

Tubulinopathy-associated dysgyria Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg

Nov 01, 2021

- -

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
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.50	T;D;T
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Pathogenic	3.1	M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
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;