Submissions for variant NM_178012.5(TUBB2B):c.1139G>A (p.Arg380His)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	RCV003326042	SCV003853431	likely pathogenic	Complex cortical dysplasia with other brain malformations 7	2023-03-23	criteria provided, single submitter	clinical testing
Invitae	RCV003689057	SCV004430374	uncertain significance	not provided	2023-02-13	criteria provided, single submitter	clinical testing	This variant disrupts the p.Arg380 amino acid residue in TUBB2B. Other variant(s) that disrupt this residue have been observed in individuals with TUBB2B-related conditions (PMID: 25140959, 31481326), which suggests that this may be a clinically significant amino acid residue. 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. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 380 of the TUBB2B protein (p.Arg380His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cortical brain malformations (Invitae). 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 TUBB2B protein function.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003326042	SCV005045252	likely pathogenic	Complex cortical dysplasia with other brain malformations 7	2024-05-22	criteria provided, single submitter	curation	The heterozygous p.Arg380His variant in TUBB2B was identified by our study in one individual with cortical dysplasia, complex, with other brain malformations 7. Trio exome analysis showed this variant to be de novo. The variant has not been previously reported in individuals with cortical dysplasia, complex, with other brain malformations 7 and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 2498169) and has been interpreted as uncertain significance by Invitae and likely pathogenic by Oxford Medical Genetics Laboratories. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in TUBB2B in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. Two additional likely pathogenic and pathogenic variants, resulting in a different amino acid change at the same position, (p.Arg380Leu and Arg380Cys), have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (Variation IDs: 160177, 1214258). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant cortical dysplasia, complex, with other brain malformations 7. ACMG/AMP Criteria applied: PS2_Supporting, PM2_Supporting, PP3_Moderate, PP2, PM5 (Richards 2015).