rs137853043

Positions:

• chr12-49185576-G-A
• chr12-49185576-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_006009.4(TUBA1A):​c.790C>T​(p.Arg264Cys) variant causes a missense change involving the alteration of a 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 7.30

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 17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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 chr12-49185576-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265283.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1, Pathogenic=2}.
• 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, 0.85
• PP5: Variant 12-49185576-G-A is Pathogenic according to our data. Variant chr12-49185576-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185576-G-A is described in Lovd as [Likely_pathogenic]. Variant chr12-49185576-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.790C>T	p.Arg264Cys	missense_variant	4/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.790C>T	p.Arg264Cys	missense_variant	4/4
TUBA1A	NM_001270400.2	c.685C>T	p.Arg229Cys	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.790C>T	p.Arg264Cys	missense_variant	4/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-2707G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly due to TUBA1A mutation Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Lab, CHRU Brest	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	Oct 04, 2022	PS4;PM1;PM2_supporting;PM5;PP2;PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 07, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2008	- -
not provided, no classification provided	literature only	GeneReviews	-	Polymicrogyria-like cortical dysplasia -
Pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	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; PMID: 20466733, PMID: 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 cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Two other variants in the same codon with changes to histidine (p.Arg264His) and glycine (p.Arg264Gly) have been reported as pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals with lissencephaly (ClinVar, PMID: 17218254, VCGS). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2016

- -

Lissencephaly Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2021

Published functional studies demonstrate a damaging effect as alpha tubulin protein harboring R264C has a diminished capacity of de novo tubulin heterodimer formation (Tian et al., 2008); Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 29671837, 28677066, 17584854, 17218254, 18199681, 18669490, 27431206, 18728072) -

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 2 years old born individual of male sex. The c.790C>T, p.(Arg264Cys) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Keays et al. Cell, 2007 PMID: 17218254. HPO-standardized clinical features were: Partial agenesis of the corpus callosum (HP:0001338); Pachygyria (HP:0001302); Dysgenesis of the cerebellar vermis (HP:0002195); Hypoplasia of the brainstem (HP:0002365); Dilation of lateral ventricles (HP:0006956); Gray matter heterotopia (HP:0002281); Congenital microcephaly (HP:0011451); Microcephaly (HP:0000252); no Seizures (-HP:0001250) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.8	H;H;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.0	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0040	D;D;.
Sift4G	Benign	0.088	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.51
MutPred		0.79		Gain of catalytic residue at P263 (P = 0);Gain of catalytic residue at P263 (P = 0);.;
MVP		0.90
MPC		4.3
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.99

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: rs137853043; hg19: chr12-49579359;