16-89935589-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_006086.4(TUBB3):c.1138C>T(p.Arg380Cys) variant causes a missense change involving the alteration of a non-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. R380P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TUBB3
NM_006086.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 2.10

Variant links:

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]

TUBB3 links:

ENSG00000198211 (HGNC:):

ENSG00000198211 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-89935590-G-C is described in Lovd as [Pathogenic].

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, 0.981

PP5

Variant 16-89935589-C-T is Pathogenic according to our data. Variant chr16-89935589-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 219257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89935589-C-T is described in Lovd as [Pathogenic]. Variant chr16-89935589-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB3	NM_006086.4 link	c.1138C>T	p.Arg380Cys	missense_variant	Exon 4 of 4	ENST00000315491.12	NP_006077.2	Q13509-1Q53G92
TUBB3	NM_001197181.2 link	c.922C>T	p.Arg308Cys	missense_variant	Exon 4 of 4		NP_001184110.1	Q13509-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB3	ENST00000315491.12 link	c.1138C>T	p.Arg380Cys	missense_variant	Exon 4 of 4	1	NM_006086.4	ENSP00000320295.7		Q13509-1
ENSG00000198211	ENST00000556922.1 link	c.2179C>T	p.Arg727Cys	missense_variant	Exon 5 of 5	2		ENSP00000451560.1		A0A0B4J269

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1461590

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727106

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jul 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 380 of the TUBB3 protein (p.Arg380Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital fibrosis of the extraocular muscles and/or cortical dysplasia (PMID: 20074521, 25131622). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 219257). 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%. Experimental studies have shown that this missense change affects TUBB3 function (PMID: 20074521). For these reasons, this variant has been classified as Pathogenic. -

Jun 15, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies indicate that R380C impacts microtubule dynamics (Tischfield et al., 2010); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32573066, 26934450, 23503589, 20074521, 25131622, 28677066, 31226147, 32169460, 26639658, 28412269, 31574570, 33144682, 20829227) -

Complex cortical dysplasia with other brain malformations 1

Pathogenic:2

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 5-Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant cortical dysplasia. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a major amino acid change. (P) 0600 - Variant is located in C-terminal domain (Protein Data Bank). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (PMIDs: 20074521; 25131622; 28677066). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function (PMID: 20074521). (P) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement

Pathogenic:1Other:1

Jan 25, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PS3_Moderate, PM6, PM2, PP2, PP3 -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Inborn genetic diseases

Pathogenic:1

Oct 11, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

.;.;D

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.7

.;.;H

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-6.2

D;D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.011

D;.;.

Sift4G

Uncertain

0.023

D;D;D

Polyphen

0.93

.;.;P

Vest4

0.87

MutPred

0.91

.;.;Loss of MoRF binding (P = 0.0076);

MVP

0.98

MPC

2.8

ClinPred

0.97

GERP RS

4.7

Varity_R

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over