rs267607165

Variant names:

• chr16-89935679-G-A
• rs267607165
• NM_006086.4:c.1228G>A

Your query was ambiguous. Multiple possible variants found:

• 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:8 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]

ENSG00000198211 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TUBB3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 4.5786 (above the threshold of 3.09). Trascript score misZ: 5.665 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
TUBB3	NM_006086.4	c.1228G>A	p.Glu410Lys	missense_variant	Exon 4 of 4	ENST00000315491.12	NP_006077.2
TUBB3	NM_001197181.2	c.1012G>A	p.Glu338Lys	missense_variant	Exon 4 of 4		NP_001184110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB3	ENST00000315491.12	c.1228G>A	p.Glu410Lys	missense_variant	Exon 4 of 4	1	NM_006086.4	ENSP00000320295.7
ENSG00000198211	ENST00000556922.1	c.2269G>A	p.Glu757Lys	missense_variant	Exon 5 of 5	2		ENSP00000451560.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 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

Aug 12, 2016

CHU Sainte-Justine Research Center, University of Montreal

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

More than 6 individuals described with this mutation, and in vitro functional studies -

Jan 08, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:2

Feb 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 410 of the TUBB3 protein (p.Glu410Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of cortical dysplasia (PMID: 28299356, 30440138, 32573066). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6967). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TUBB3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Sep 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Complex cortical dysplasia with other brain malformations 1 Pathogenic:2

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2. -

Jun 04, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TUBB3-Releated Disorders Pathogenic:1

Jun 19, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

TUBB3-related disorder Pathogenic:1

May 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;