Submissions for variant NM_178012.5(TUBB2B):c.908G>A (p.Cys303Tyr)

dbSNP: rs2113819019

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV002226852	SCV002505738	likely pathogenic	Complex cortical dysplasia with other brain malformations 7	2021-08-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002226852	SCV005045251	likely pathogenic	Complex cortical dysplasia with other brain malformations 7	2024-05-22	criteria provided, single submitter	curation	The heterozygous p.Cys303Tyr variant in TUBB2B was identified by our study in 2 siblings with cortical dysplasia, complex, with other brain malformations 7. Trio exome analysis showed this variant to be de novo in both siblings. 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: 1679255) and has been interpreted as likely pathogenic by Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet. 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. 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_Moderate, PM2_Supporting, PP3_Moderate, PP2 (Richards 2015).