Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001379085 | SCV001576818 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2020-08-31 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.His315 amino acid residue in TGFBR1. Other variant(s) that disrupt this residue have been observed in individuals with TGFBR1-related conditions (PMID: 19542084), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with Loeys Dietz syndrome (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with tyrosine at codon 315 of the TGFBR1 protein (p.His315Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. |
| Victorian Clinical Genetics Services, |
RCV004594277 | SCV005085997 | likely pathogenic | Loeys-Dietz syndrome 1 | 2023-07-17 | 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 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) 0115 - Variants in this gene are known to have variable expressivity. There is considerable variability in the phenotype, from mild features to severe systemic abnormalities (PMID: 32339686). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD v2 (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Protein kinase domain (DECIPHER). (I) 0704 – Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(His315Arg) has been identified in two independent families. In one of these families, the variant was found to segregate with disease in three family members with thoracic aortic aneurysms and dissections (TAAD) (ClinVar, PMID: 19542084). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been identified de novo in a Loeys Dietz syndrome affected individual (ClinVar). (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |