Submissions for variant NM_006086.4(TUBB3):c.136C>T (p.Arg46Trp)

dbSNP: rs1555625363

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656083	SCV000598581	likely pathogenic	Complex cortical dysplasia with other brain malformations 1	2017-09-01	criteria provided, single submitter	research	this variant was indentified in an individual with malformations of cortical development
DASA	RCV001824143	SCV002073749	likely pathogenic	Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement	2022-02-05	criteria provided, single submitter	clinical testing	The c.136C>T;p.(Arg46Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 438582; PMID: 29269699; 29706646) - PS4_supporting. This variant is not present in population databases (rs1555625363; gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo; but without confirmation of paternity and maternity (PMID: 29269699; 29706646) - PM6. Missense variant in TUBB3 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic.
GeneDx	RCV002461261	SCV002756622	pathogenic	not provided	2022-11-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 29706646, 29269699, 20829227)
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV003126774	SCV003803900	likely pathogenic	Developmental disorder	2021-06-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002461261	SCV004184625	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	TUBB3: PS2:Very Strong, PM2, PS4:Moderate, PM5:Supporting, PP2, PP3
Invitae	RCV002461261	SCV004296443	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 438582). This missense change has been observed in individual(s) with clinical features of TUBB3-related conditions (PMID: 29269699, 29706646). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 46 of the TUBB3 protein (p.Arg46Trp).