rs267607165

Positions:

• chr16-89935679-G-A
• chr16-89935679-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_006086.4(TUBB3):​c.1228G>A​(p.Glu410Lys) 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TUBB3 NM_006086.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.92

Genes affected

TUBB3 (HGNC:20772): (tubulin beta 3 class III) This gene encodes a class III member of the beta tubulin protein family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. This protein is primarily expressed in neurons and may be involved in neurogenesis and axon guidance and maintenance. Mutations in this gene are the cause of congenital fibrosis of the extraocular muscles type 3. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBB3. . Gene score misZ 4.5786 (greater than the threshold 3.09). Trascript score misZ 5.665 (greater than threshold 3.09). GenCC has associacion of gene with tubulinopathy-associated dysgyria, complex cortical dysplasia with other brain malformations 1, congenital fibrosis of extraocular muscles, fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 16-89935679-G-A is Pathogenic according to our data. Variant chr16-89935679-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89935679-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB3	NM_006086.4	c.1228G>A	p.Glu410Lys	missense_variant	4/4	ENST00000315491.12	NP_006077.2
TUBB3	NM_001197181.2	c.1012G>A	p.Glu338Lys	missense_variant	4/4		NP_001184110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB3	ENST00000315491.12	c.1228G>A	p.Glu410Lys	missense_variant	4/4	1	NM_006086.4	ENSP00000320295	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 08, 2010	- -
Pathogenic, no assertion criteria provided	research	CHU Sainte-Justine Research Center, University of Montreal	Aug 12, 2016	More than 6 individuals described with this mutation, and in vitro functional studies -
not provided, no classification provided	literature only	GeneReviews	-	- -

Complex cortical dysplasia with other brain malformations 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 04, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2. -

TUBB3-Releated Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Jun 19, 2019

This variant has been previously reported as a de novo heterozygous change in patients with hypoplasia of oculomotor nerves, hypoplasia of the corpus callosum, developmental delay, facial weakness, and cyclic vomiting (PMID: 20074521, 23378218, 25559402, 29289389). Functional studies have shown that the c.1228G>A (p.Glu410Lys) variant inhibits axonal transport of vesicles and mitochondria (PMID: 23503589). This variant is in the H12 helix of beta-tubulin and changes the negative charge on the surface of the microtubule, which is important for binding to kinesin superfamily motor proteins (KIFs). The disrupted binding of axonal transport KIFs to microtubules alters the localization of KIFs in neurons and inhibits axon elongation (PMID: 23503589). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1228G>A (p.Glu410Lys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples showed the mother is negative and the father is negative for this variant, indicating this likely occurred as a de novo event. Based on the available evidence, the c.1228G>A (p.Glu410Lys) variant is classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2022

Published functional studies demonstrate E410K affected microtubule polymerization and depolymerization rates as well as kinesin interactions on microtubules and reduced axonal transport of mitochondria in peripheral neurons independent of tubulin isoform (Tischfield et al., 2010; Niwa et al., 2013); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29289389, 30272120, 23378218, 25559402, 28299356, 30440138, 29382549, 28677066, 31226147, 20074521, 32573066, 20301522, 20829227, 32005694, 23503589) -

TUBB3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2023

The TUBB3 c.1228G>A variant is predicted to result in the amino acid substitution p.Glu410Lys. This variant has been reported to occur de novo in multiple individuals affected by what is known as 'TUBB3 E410K syndrome' (Chew et al. 2013. PubMed ID: 23378218; Romaniello et al. 2017. PubMed ID: 28677066; Tischfield et al. 2010. PubMed ID: 20074521; Grant et al. 2018. PubMed ID: 30272120). Patients were reported to have congenital fibrosis of the extraocular muscles, facial weakness, developmental delay, and possible peripheral neuropathy; however, early signs of this disorder may include fetal distress, stridor, and/or tracheomalacia (Chew et al. 2013. PubMed ID: 23378218). In vitro functional studies indicate that the p.Glu410Lys change significantly inhibits axonal transport of vesicles and mitochondria (Niwa et al. 2013. PubMed ID: 23503589). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret c.1228G>A (p.Glu410Lys) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	.;.;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.1	.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.91	.;.;P
Vest4		0.90
MutPred		0.80		.;.;Gain of ubiquitination at E410 (P = 0.009);
MVP		1.0
MPC		1.7
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.56
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: rs267607165; hg19: chr16-90002087; COSMIC: COSV100206073; COSMIC: COSV100206073;