12-49185725-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_006009.4(TUBA1A):c.641G>A(p.Arg214His) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R214C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.25

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 16 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, 2 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 chr12-49185725-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, TUBA1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818
• PP5: Variant 12-49185725-C-T is Pathogenic according to our data. Variant chr12-49185725-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185725-C-T is described in Lovd as [Likely_pathogenic]. Variant chr12-49185725-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.641G>A	p.Arg214His	missense_variant	4/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.641G>A	p.Arg214His	missense_variant	4/4
TUBA1A	NM_001270400.2	c.536G>A	p.Arg179His	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.641G>A	p.Arg214His	missense_variant	4/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-2558C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly due to TUBA1A mutation Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Aug 01, 2017	De novo missense variant identified in a female patient with severe ID, severe epilepsy, developmental regression, scoliosis, hypotonia, MRI: agenesis of corpus callosum, Dandy-Walker malformation, opticus hypoplasia, delayed bone age. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 25, 2022	ACMG classification criteria: PS4 strong, PM2 moderated, PM6 moderated, PP2 supporting, PP3 supporting -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Arg214His variant in TUBA1A was identified by our study in one individual with lissencephaly. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The TUBA1A gene has a low rate of benign missense variation, supporting that a change in this position may not be tolerated. This variant has been reported in ClinVar (Variation ID: 372542). Multiple reports of de novo inheritance of this variant were reported in ClinVar and the literature. In summary, the p.Arg214His variant is pathogenic based off of our findings, multiple de novo reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PS2, PM6_Strong, PP2 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372542). Different missense changes at the same codon (p.Arg214Cys, p.Arg214Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000432708, VCV001187068). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 02, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2021	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TUBA1A function (PMID: 26130693). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). ClinVar contains an entry for this variant (Variation ID: 372542). This missense change has been observed in individual(s) with lissencephaly, including several cases in which the variant was observed to be de novo (PMID: 24860126, 26130693, 29158550; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 214 of the TUBA1A protein (p.Arg214His). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2020	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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: 32570172, 30087272, 30744660, 28677066, 26934450, 24860126, 25059107, 26130693, 29158550) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2018	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2020

The c.641G>A (p.R214H) alteration is located in exon 4 (coding exon 4) of the TUBA1A gene. This alteration results from a G to A substitution at nucleotide position 641, causing the arginine (R) at amino acid position 214 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the TUBA1A c.641G>A alteration was not observed, with coverage at this position. This alteration was reported de novo in multiple patients with developmental delay and abnormal brain MRI findings (Bahi-Buisson, 2014; Oegema, 2015; Hedebrand, 2019). The p.R214 amino acid is conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional analysis in HEK93 cells following cold-induced depolymerization, demonstrated that the p.R214H alteration showed reduced microtubule reintegration compared to wildtype, suggesting that the arginine-to-histidine substitution subtly perturbs the rate that affected heterodimers integrate into growing microtubules (Oegema, 2015). The in silico prediction for the p.R214H alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

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 51 months old born individual of female sex. The c.641G>A, p.(Arg214His) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Oegema et al. Hum Mol Genet, 2015 PMID: 26130693. HPO-standardized clinical features were: Partial agenesis of the corpus callosum (HP:0001338); Other (NA); Cerebellar vermis hypoplasia (HP:0001320); no Abnormal morphology of the hippocampus (HP:0025100); Dilation of lateral ventricles (HP:0006956); Microcephaly (HP:0000252); Generalized tonic-clonic seizures (HP:0002069) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T;T;.;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.5	L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0070	D;D;.;.
Sift4G	Benign	0.23	T;T;T;.
Polyphen		0.0040	B;B;.;.
Vest4		0.53
MutPred		0.46		Gain of catalytic residue at L217 (P = 0.002);Gain of catalytic residue at L217 (P = 0.002);.;.;
MVP		0.90
MPC		2.2
ClinPred		0.95	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.91

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: rs1057517843; hg19: chr12-49579508;