Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000461373 | SCV000548325 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2023-05-02 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 408560). This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg157*) in the TGFBR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TGFBR1 are known to be pathogenic (PMID: 21358634). |
| Victorian Clinical Genetics Services, |
RCV002470860 | SCV002767454 | pathogenic | Multiple self-healing squamous epithelioma | 2021-05-06 | 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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with multiple self-healing squamous epithelioma (MIM#132800) (PMID: 21358634). Only missense variants with a suspected dominant negative mechanism of disease have been associated with Loeys–Dietz syndrome (MIM#609192) (PMID: 29706644). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity. While these variants have been reported with conflicting classifications (ClinVar), they are consistently reported as pathogenic for multiple self-healing squamous epithelioma. These individuals do not display features of Loeys–Dietz syndrome, which is exclusively caused by missense variants (PMID: 29706644, PMID: 33256177). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as pathogenic (ClinVar) and as a VUS (LOVD). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |