rs864321717

Positions:

• chr16-89935589-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000315491.12(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. R380H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBB3 ENST00000315491.12 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 2.10

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 19 ACMG points.

• PM1: In a helix (size 15) in uniprot entity TBB3_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in ENST00000315491.12
• 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 ClinVar as [Likely_pathogenic]. Clinvar id is 1320230.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.981
• 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/exons	MANE	Protein	UniProt
TUBB3	NM_006086.4	c.1138C>T	p.Arg380Cys	missense_variant	4/4	ENST00000315491.12	NP_006077.2
TUBB3	NM_001197181.2	c.922C>T	p.Arg308Cys	missense_variant	4/4		NP_001184110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB3	ENST00000315491.12	c.1138C>T	p.Arg380Cys	missense_variant	4/4	1	NM_006086.4	ENSP00000320295	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461590 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 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.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TUBB3 function (PMID: 20074521). 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. ClinVar contains an entry for this variant (Variation ID: 219257). 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. This variant is not present in population databases (gnomAD no frequency). 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). -

Complex cortical dysplasia with other brain malformations 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	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 -
Pathogenic, criteria provided, single submitter	research	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 25, 2022	PS4, PS3_Moderate, PM6, PM2, PP2, PP3 -
not provided, no classification provided	literature only	GeneReviews	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;.;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.7	.;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
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	D
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

Other links and lift over

dbSNP: rs864321717; hg19: chr16-90001997;