Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV002273008 | SCV002557548 | likely pathogenic | Intellectual disability, autosomal dominant 41 | 2021-05-06 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with TBL1XR1-related intellectual disability (MIM#616944). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Several patients show different neurological phenotypes, such as intellectual disability, autism, epilepsy, schizophrenia and Rett features however, in only a few of them are dysmorphic features reported (PMID: 33527360). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to alanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Exac), within the WD40 domain (NCBI). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an individual with intellectual disability, autism, epilepsy and dysmorphic features (PMID: 32901917). (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). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| 3billion, |
RCV002273008 | SCV003842074 | uncertain significance | Intellectual disability, autosomal dominant 41 | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TBL1XR1 -related disorder (PMID: 32901917). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. |