Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000657969 | SCV000779740 | pathogenic | not provided | 2021-06-04 | criteria provided, single submitter | clinical testing | Published functional studies suggest a damaging effect; P243L variant causes shortening of neurites and that the P243 residue plays a role in the intradimer interaction of the tubulin proteins (Zheng et al., 2017); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 32203252, 28835377, 27535533) |
| Laboratory of Molecular Genetics |
RCV000657969 | SCV000920517 | likely pathogenic | not provided | 2018-08-08 | criteria provided, single submitter | clinical testing | |
| Hudson |
RCV003303088 | SCV004009656 | uncertain significance | Complex cortical dysplasia with other brain malformations 5 | 2023-04-17 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV000657969 | SCV004641529 | uncertain significance | not provided | 2024-05-15 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 243 of the TUBB2A protein (p.Pro243Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of cortical malformation syndrome (PMID: 32203252). ClinVar contains an entry for this variant (Variation ID: 546138). 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 TUBB2A protein function with a positive predictive value of 80%. 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. |
| Victorian Clinical Genetics Services, |
RCV003303088 | SCV005399850 | pathogenic | Complex cortical dysplasia with other brain malformations 5 | 2024-10-10 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with cortical dysplasia, complex, with other brain malformations 5, (MIM#615763). Functional studies have shown missense variants to cause weakened incorporation into cytoskeleton, and potentially impaired heterodimer formation indicating loss of function. However, the mutational spectrum is more suggestive of a dominant negative mechanism (PMID: 24702957). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (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 (low missense variation in gnomAD). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Pro243Arg) has one VUS report in ClinVar. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant is reported as conflicting in ClinVar, and has been reported de novo in an individual with infantile-onset epilepsy and global developmental delay in the literature (PMID: 32203252). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 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 |