Submissions for variant NM_006086.4(TUBB3):c.533C>T (p.Thr178Met)

dbSNP: rs747480526

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254864	SCV000322117	pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	Published functional studies suggest that T178M impacts the function of the protein (Poirier et al., 2010, Park et al., 2021); Not observed at a significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 26639658, 24860126, 21292473, 22669706, 26934450, 28726809, 29261186, 29382549, 31226147, 32169460, 20829227, 34869359)
Ambry Genetics	RCV000624084	SCV000743060	likely pathogenic	Inborn genetic diseases	2017-11-09	criteria provided, single submitter	clinical testing
Invitae	RCV000254864	SCV001503250	pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TUBB3 function (PMID: 20829227, 29382549). 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: 265335). This missense change has been observed in individual(s) with cortical dysplasia with other brain malformations (PMID: 20829227, 28726809, 29261186). In at least one individual the variant was observed to be de novo. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 178 of the TUBB3 protein (p.Thr178Met).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000023203	SCV002557962	pathogenic	Complex cortical dysplasia with other brain malformations 1	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with cortical dysplasia, complex, with other brain malformations 1 (MIM#614039) (PMID: 31219644). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missene variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in one de novo individual with malformation of the cortical development and another heterozygous individual with fetal brain malformation (PMID: 20829227, 34869359). It has also been reported as pathogenic, likely pathogenic and VUS in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies using patient fibroblasts showed this variant reduced microtubule stablity (PMID: 20829227). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000023203	SCV000044494	pathogenic	Complex cortical dysplasia with other brain malformations 1	2010-11-15	no assertion criteria provided	literature only